Therapeutic substituted guanidines

ABSTRACT

The present invention provides therapeutically useful substituted guanidines of the following Formula: ##STR1## and methods of treatment and pharmaceutical compositions that utilize or comprise one or more of such guanidines.

This is a continuation of International Application PCT/US94/06008, withan international filing date of May 27, 1994, now abandoned, and whichis a continuation-in-part of U.S. application Ser. No. 08/068,522, filedMay 27, 1993, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to certain substituted guanidines, andmethods of treatment and pharmaceutical compositions that utilize orcomprise one or more such guanidines.

2. Background

A number of substituted guanidines have been reported. See, e.g., U.S.Pat. Nos. 1,411,731, 1,422,506, 1,597,233, 1,642,180, 1,672,431,1,730,388, 1,756,315, 1,795,739, 1,850,682, 2,145,214, 2,254,009,2,633,474, 3,117,994, 3,140,231, 3,159,676, 3,228,975, 3,248,426,3,252,816, 3,283,003, 3,270,054, 3,301,755, 3,320,229, 3,301,775,3,409,669, 3,479,437, 3,547,951, 3,639,477, 3,681,457, 3,769,427,3,784,643, 3,803,324, 3,908,013, 3,949,089, 3,975,533, 3,976,787,4,060,640, 4,014,934, 4,161,541, 4,709,094, 4,906,779, 5,093,525,5,190,976 and 5,262,568; PCT applications WO 90/12575, WO 91/12797, WO91/18868, and WO 92/14697; and H. W. Geluk, et al., J. Med. Chem.,12:712 (1969).

The amino acid L-glutamate is widely thought to act as a chemicaltransmitter substance at excitatory synapses within the central nervoussystem. Neuronal responses to glutamate are complex and appear to bemediated by at least three different receptor types, i.e., KA, QA andNMDA subtypes, each being named for their relatively specific ligands,i.e., kainic acid, quisaqualic acid and N-methyl-D-aspartic acid,respectively. An amino acid which activates one or more of thesereceptor types is referred to as an excitatory amino acid (EAA).

The NMDA subtype of excitatory amino acid receptors is activated duringnormal excitatory synaptic transmission in the brain. Activation of NMDAreceptors under normal conditions is responsible for the phenomena oflong-term potentiation, a memory-like phenomenon, at excitatorysynapses. Excessive excitation of neurons occurs in epileptic seizuresand it has been shown that over-activation of NMDA receptors contributesto the pathophysiology of epilepsy.

NMDA receptors are also strongly involved in nerve cell death whichoccurs following brain or spinal cord ischemia. Upon the occurrence ofischemic brain insults such as stroke or heart attack, an excessiverelease of endogenous glutamate occurs, resulting in theover-stimulation of NMDA receptors. Associated with the NMDA receptorsis an ion channel. The recognition site, i.e., the NMDA receptor, isexternal to the ion channel. When glutamate interacts with the NMDAreceptor, it causes the ion channel to open, thereby permitting a flowof cations across the cell membrane, e.g., Ca²⁺ and Na⁺ into the celland K⁺ out of the cell. It is believed that this flux of ions,especially the influx of Ca²⁺ ions, caused by the interaction ofglutamate with the NMDA receptor, plays an important role in nerve celldeath. See, e.g., S. M. Rothman, et al., Trends in Neurosci.,10(7):299-302 (1987).

Agents which block responses to NMDA receptor activation therefore havetherapeutic uses in the treatment of neurological disorders such asepilepsy and also in the prevention of nerve cell death resulting fromhypoxia or hypoglycemia or following brain ischemia which occurs duringstroke, trauma and heart attack. A number of disorders of the nervoussystem are associated with neurodegeneration that may be caused byoveractivation of NMDA receptors. Antagonists of NMDA receptor-mediatedresponses have potential therefore for the treatment of such disordersas Alzheimer's disease, Parkinson's disease, Huntington's disease,Amyotrophic Lateral Sclerosis, Down's Syndrome and Korsakoff's disease.

Research on the NMDA receptor-ion channel complex has led todetermination of a receptor site within the ion channel known as the PCPreceptor. See J. P. Vincent, et al., Proc. Natl. Acad. Sci. USA,76:4678-4682 (1979); S. R. Zukin, et al., Proc. Natl. Acad. Sci. USA,76:5372-5376 (1979); M. S. Sonders, et al., Trends in Neurosci.,11(1):37-40 (1988); and N. A. Anis, et al., Br. J. Pharmacol.,79:565-575 (1983). A compound which binds to the PCP receptor can act asan ion channel blocker, thereby interrupting the flow of ions throughthe cell membrane. In this manner, agents which interact with the PCPreceptor act as non-competitive antagonists reducing the agonist actionof glutamate at the NMDA receptor.

Known PCP receptor ligands include PCP, i.e., Phencyclidine, analoguessuch as 1-[1-(2-thienyl)-cyclohexyl]-piperidine (TCP), benzomorphan(sigma) opiates, and(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5,10-imine (i.e.,the drug MK-801, see U.S. Pat. No. 4,399,141). See, also, E. H. F. Wong,et al., Proc. Natl. Acad. Sci. USA, 83:7104-7108 (1986), and W. J.Thompson, et al., J. Med. Chem., 33:789-808 (1990).

SUMMARY OF THE INVENTION

The present invention provides substituted guanidines of Formula I:##STR2## wherein R, R¹ and R² are each independently hydrogen,substituted or unsubstituted alkyl having from 1 to about 20 carbonatoms, substituted or unsubstituted alkenyl having from 2 to about 20carbon atoms, substituted or unsubstituted alkynyl having from 2 toabout 20 carbon atoms, substituted or unsubstituted alkoxy having from 1to about 20 carbon atoms, substituted or unsubstituted alkylthio havingfrom 1 to about 20 carbon atoms, substituted or unsubstituted aminoalkylhaving from 1 to about 20 carbon atoms, substituted or unsubstitutedcarbocyclic aryl having at least about 6 ring carbon atoms, substitutedor unsubstituted aralkyl having at least about 6 carbon ring atoms, or asubstituted or unsubstituted heteroaromatic or heteroalicyclic grouphaving from 1 to 3 rings, 3 to 8 ring members in each ring and from 1 to3 hetero atoms;

R³ and R⁴ are each independently halogen, hydroxyl, azido, substitutedor unsubstituted alkyl having from 1 to about 20 carbon atoms,substituted or unsubstituted alkenyl having from 2 to about 20 carbonatoms, substituted or unsubstituted alkynyl having from 2 to about 20carbon atoms, substituted or unsubstituted alkoxy having from 1 to about20 carbon atoms, substituted or unsubstituted alkylthio having from 1 toabout 20 carbon atoms, substituted or unsubstituted aminoalkyl havingfrom 1 to about 20 carbon atoms, substituted or unsubstitutedcarbocyclic aryl having at least about 6 ring carbon atoms, orsubstituted or unsubstituted aralkyl having at least about 6 ring carbonatoms;

each R⁵ substituent is independently halogen, hydroxyl, azido,substituted or unsubstituted alkyl having from 1 to about 20 carbonatoms, substituted or unsubstituted alkenyl having from 2 to about 20carbon atoms, substituted or unsubstituted alkynyl having from 2 toabout 20 carbon atoms, substituted or unsubstituted alkoxy having from 1to about 20 carbon atoms, substituted or unsubstituted alkylthio havingfrom 1 to about 20 carbon atoms, substituted or unsubstituted aminoalkylhaving from 1 to about 20 carbon atoms, substituted or unsubstitutedcarbocyclic aryl having at least about 6 ring carbon atoms, orsubstituted or unsubstituted aralkyl having at least about 6 ring carbonatoms;

n is an integer of from 0 to 3; and pharmaceutically acceptable saltsthereof.

In another aspect, the invention provides compounds of the followingFormula II: ##STR3## wherein R, R¹ and R² are each independentlyhydrogen, substituted or unsubstituted alkyl having from 1 to about 20carbon atoms, substituted or unsubstituted alkenyl having from 2 toabout 20 carbon atoms, substituted or unsubstituted alkynyl having from2 to about 20 carbon atoms, substituted or unsubstituted alkoxy havingfrom 1 to about 20 carbon atoms, substituted or unsubstituted alkylthiohaving from 1 to about 20 carbon atoms, substituted or unsubstitutedalkylsulfinyl having from 1 to about 20 carbon atoms, substituted orunsubstituted alkylsulfonyl having from 1 to about 20 carbon atoms,substituted or unsubstituted aminoalkyl having from 1 to about 20 carbonatoms, substituted or unsubstituted carbocyclic aryl having at least 6ring carbon atoms, substituted or unsubstituted aralkyl having at least6 ring carbon atoms, or a substituted or unsubstituted heteroaromatic orheteroalicyclic group having 1 to 3 rings, 3 to 8 ring members in eachring and 1 to 3 hetero atoms;

R³, R⁴, and each R⁵ substituent are each independently halogen,hydroxyl, azido, substituted or unsubstituted alkyl having from 1 toabout 20 carbon atoms, substituted or unsubstituted alkenyl having from2 to about 20 carbon atoms, substituted or unsubstituted alkynyl havingfrom 2 to about 20 carbon atoms, substituted or unsubstituted alkoxyhaving from 1 to about 20 carbon atoms, substituted or unsubstitutedalkylthio having from 1 to about 20 carbon atoms, substituted orunsubstituted alkylsulfinyl having from 1 to about 20 carbon atoms,substituted or unsubstituted alkylsulfonyl having from 1 to about 20carbon atoms, substituted or unsubstituted aminoalkyl having from 1 toabout 20 carbon atoms, substituted or unsubstituted carbocyclic arylhaving about 6 or more ring carbon atoms, or substituted orunsubstituted aralkyl having about 6 or more ring carbon atoms; n is aninteger of from 0-3; or a pharmaceutically acceptable salt thereof.Thus, Formula II is defined the same as above for Formula I except R,R¹, R², R³, R⁴, R⁵ of Formula II each also may be independently selectedfrom substituted or unsubstituted alkylsulfoxide having from 1 to about20 carbon atoms and substituted or unsubstituted alkylsulfonyl havingfrom 1 to about 20 carbon atoms.

Preferred compounds of Formulas I and II exhibit a high affinity for thePCP receptor. The phrase "high affinity for the PCP receptor" as 10 usedherein means the compound exhibits an IC₅₀ of 1 μM or less in a typicalPCP receptor binding assay such as described in Example 74 whichfollows, more preferably an IC₅₀ of 0.5 μM or less in such a PCPreceptor assay. For reasons discussed below, for at least sometherapeutic applications, further preferred are those compounds ofFormulas I and II that exhibit such high affinity for the PCP receptoras well as high affinity for the sigma receptor. The phrase "highaffinity for the sigma receptor" as used herein means the compoundexhibits an IC₅₀ of 1 μM or less in a typical sigma receptor bindingassay such as described in Example 75 which follows, more preferably anIC₅₀ of 0.5 μM or less in such a sigma receptor assay.

The substituted guanidines of the invention are useful for a number oftherapeutic applications. Accordingly, the present invention includesmethods for treatment and/or prophylaxis of neurological conditions suchas epilepsy, neurodegenerative conditions and/or nerve cell deathresulting from e.g. hypoxia, hypoglycemia, brain or spinal chordischemia, brain or spinal chord trauma, and the like. Compounds ofFormulas I and II also are useful to treat and/or prevent variousneurodegenerative diseases such as Parkinson's disease, Huntington'sdisease, Amyotrophic Lateral Sclerosis, Alzheimer's disease, Down'sSyndrome and Korsakoff's disease. The methods of the invention ingeneral comprise administration of a therapeutically effective amount ofone or more compounds of Formula I or Formula II to an animal, includinga mammal, particularly a human.

The invention also provides pharmaceutical compositions that compriseone or more compounds of Formula I or Formula II and a suitable carrier.

Other aspects of the invention are disclosed infra.

DETAILED DESCRIPTION OF THE INVENTION

Suitable halogen substituent groups of compounds of Formulas I and II asdefined above (i.e. compounds of the invention) include F, Cl, Br and I.It is intended that references herein to Formulas I and II, orreferences to compounds of the invention, apply equally to compounds ofFormulas Ia, Ib, Ic, IIa, IIb and IIc as those formulas are definedherein. Hence, suitable and preferred substituent groups of Formulas Iand II as identified herein, are also suitable and preferred substituentgroups of compounds of Formulas Ia, Ib, Ic, IIa, IIb and IIc. Alkylgroups of compounds of Formulas I and II preferably have from 1 to about12 carbon atoms, more preferably 1 to about 8 carbon atoms, still morepreferably 1 to about 6 carbon atoms, even more preferably 1, 2, 3 or 4carbon atoms. Methyl, ethyl and propyl including isopropyl areparticularly preferred alkyl groups. As used herein, the term alkylunless otherwise modified refers to both cyclic and noncyclic groups,although of course cyclic groups will comprise at least three carbonring members. Straight or branched chain noncyclic alkyl groups aregenerally more preferred than cyclic groups. Preferred alkenyl andalkynyl groups of compounds of the invention have one or moreunsaturated linkages and from 2 to about 12 carbon atoms, morepreferably 2 to about 8 carbon atoms, still more preferably 2 to about 6carbon atoms, even more preferably 2, 3 or 4 carbon atoms. The termsalkenyl and alkynyl as used herein refer to both cyclic and noncyclicgroups, although straight or branched noncyclic groups are generallymore preferred. Preferred alkoxy groups of compounds of Formulas I andII include groups having one or more oxygen linkages and from 1 to about12 carbon atoms, more preferably from 1 to about 8 carbon atoms, andstill more preferably 1 to about 6 carbon atoms, even more preferably 1,2, 3 or 4 carbon atoms. Preferred alkylthio groups of compounds ofFormulas I and II include those groups having one or more thioetherlinkages and from 1 to about 12 carbon atoms, more preferably from 1 toabout 8 carbon atoms, and still more preferably 1 to about 6 carbonatoms. Alkylthio groups having 1, 2, 3 or 4 carbon atoms areparticularly preferred. Preferred alkylsulfinyl groups of compounds ofthe invention include those groups having one or more sulfoxide (SO)groups and from 1 to about 12 carbon atoms, more preferably from 1 toabout 8 carbon atoms, and still more preferably 1 to about 6 carbonatoms. Alkylsulfinyl groups having 1, 2, 3 or 4 carbon atoms areparticularly preferred. Preferred alkylsulfonyl groups of compounds ofthe invention include those groups having one or more sulfonyl (SO₂)groups and from 1 to about 12 carbon atoms, more preferably from 1 toabout 8 carbon atoms, and still more preferably 1 to about 6 carbonatoms. Alkylsulfonyl groups having 1, 2, 3 or 4 carbon atoms areparticularly preferred. Preferred aminoalkyl groups include those groupshaving one or more primary, secondary and/or tertiary amine groups, andfrom 1 to about 12 carbon atoms, more preferably 1 to about 8 carbonatoms, still more preferably 1 to about 6 carbon atoms, even morepreferably 1, 2, 3 or 4 carbon atoms. Secondary and tertiary aminegroups are generally more preferred than primary amine moieties.Suitable heteroaromatic groups of compounds of Formula I and Formula IIcontain one or more N, O or S atoms and include, e.g., coumarinylincluding 8-coumarinyl, quinolinyl including 8-quinolinyl, pyridyl,pyrazinyl, pyrimidyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl,imidazolyl, indolyl, benzofuranyl and benzothiazol. Suitableheteroalicyclic groups of compounds of Formula I and Formula II containone or more N, O or S atoms and include, e.g., tetrahydrofuranyl,tetrahydropyranyl, piperidinyl, morpholino and pyrrolindinyl groups.Suitable carbocyclic aryl groups of compounds of Formula I and FormulaII include single and multiple ring compounds, including multiple ringcompounds that contain separate and/or fused aryl groups. Typicalcarbocyclic aryl groups contain 1 to 3 separate or fused rings and from6 to about 18 carbon ring atoms. Specifically preferred carbocyclic arylgroups include phenyl including 3-substituted phenyl, 2,5-substitutedphenyl, 2,3,5-substituted and 2,4,5-substituted phenyl, particularlywhere the phenyl substituents are independently selected from the samegroup as defined above for R³ --R⁵ ; naphthyl including 1-naphthyl and2-naphthyl; biphenyl; phenanthryl; and anthracyl. Suitable aralkylgroups of compounds of Formula I and Formula II include single andmultiple ring compounds, including multiple ring compounds that containseparate and/or fused aryl groups. Typical aralkyl groups contain 1 to 3separate or fused rings and from 6 to about 18 carbon ring atoms.Preferred aralkyl groups include benzyl and methylenenaphthyl (--CH₂-naphthyl).

Said substituted R, R¹, R², R³, R⁴ and R⁵ groups of Formula I or FormulaII (as well as substituted groups of Formulas Ia-Ic and IIa-IIc asspecified below) may be substituted at one or more available positionsby one or more suitable groups such as, e.g., halogen such as fluoro,chloro, bromo and iodo; cyano; hydroxyl; nitro; azido; alkanoyl such asa C₁₋₆ alkanoyl group such as acyl and the like; carboxamido; alkylgroups including those groups having 1 to about 12 carbon atoms or from1 to about 6 carbon atoms and more preferably 1-3 carbon atoms; alkenyland alkynyl groups including groups having one or more unsaturatedlinkages and from 2 to about 12 carbon or from 2 to about 6 carbonatoms; alkoxy groups having those having one or more oxygen linkages andfrom 1 to about 12 carbon atoms or 1 to about 6 carbon atoms; aryloxysuch as phenoxy; alkylthio groups including those moieties having one ormore thioether linkages and from 1 to about 12 carbon atoms or from 1 toabout 6 carbon atoms; and aminoalkyl groups such as groups having one ormore N atoms and from 1 to about 12 carbon atoms or from 1 to about 6carbon atoms.

It should be understood that alkoxy, alkylthio, alkylsulfinyl,alkylsulfonyl and aminoalkyl substituent groups described above includegroups where a hetero atom is directly bonded to a ring system, such asa carbocyclic aryl group or a heterocyclic group, as well as groupswhere a hetero atom of the group is spaced from such ring system by analkylene linkage, e.g. of 1 to about 4 carbon atoms.

Preferred phenyl ring substituents R³, R⁴ and R⁵ of Formulas I and II(as well as phenyl ring substituents of Formulas Ia-Ic and IIa-IIc asspecified below) include halogen, particularly F, Cl and Br, hydroxyl,azido, substituted or unsubstituted alkyl including halogenated alkyl,substituted and unsubstituted alkoxy including halogenated alkoxy, andsubstituted and unsubstituted alkylthio. Typically preferred phenyl ringsubstituents have 1 to 4 carbon atoms with methyl, ethyl, and propylincluding isopropyl being particularly preferred. Halogen-substitutedalkyl and alkoxy groups are also particularly preferred includingfluoroalkyl having 1, 2, 3 or 4 carbon atoms such as trifluoromethyl andfluoro-substituted alkoxy having 1, 2, 3 or 4 carbon atoms such astrifluoromethoxy (--OCF₃). Methylthio (--SCH₃) and ethylthio (--SCH₂CH₃) are also particularly preferred phenyl ring substituents.

Preferred compounds of the invention include trisubstituted compoundswhere one of the guanidine substituents R, R¹ and R² of the abovedefined Formulas (or the corresponding guanidine substituents ofFormulas Ia-Ic and IIa-IIc as specified below) is hydrogen and the othertwo substituents are other than hydrogen, more preferably where R or R¹is heterocyclic aryl or carbocyclic aryl, still more preferably where Ris substituted or unsubstituted heterocyclic aryl or substituted orunsubstituted carbocyclic aryl and one of R¹ and R² is hydrogen and oneof R¹ and R² is substituted or unsubstituted alkyl. Also preferred areN,N'-disubstituted compounds, i.e. where one of R and R¹ of Formulas Ior II (or the corresponding guanidine substituents of Formulas Ia-Ic andIIa-IIc) is hydrogen and R² is hydrogen, preferably where R issubstituted or unsubstituted heterocyclic aryl or substituted orunsubstituted carbocyclic aryl and R¹ and R² are hydrogen. Alsopreferred are N,N,N',N'-tetrasubstituted compounds, i.e. where each ofR, R¹ and R² substituents of Formulas I or II (or the correspondingguanidine substituents of Formulas Ia-Ic and IIa-IIc) is other thanhydrogen, preferably where R or R¹ is substituted or unsubstitutedheterocyclic aryl or substituted or unsubstituted carbocyclic aryl, morepreferably where R is substituted or unsubstituted heterocyclic aryl orsubstituted or unsubstituted carbocyclic aryl and R¹ and R² are eachsubstituted or unsubstituted alkyl. In any event, at least one of thesubstituents R and R¹ of compounds of Formula I or II generally will beother than hydrogen.

Preferred R³, R⁴ and R⁵ alkylsulfinyl groups of compounds of Formula II(as well as phenyl ring alkylsulfinyl groups of compounds of FormulasIIa-IIc as specified below) typically have one or more sulfoxide groups,more typically, one or two sulfoxide groups and from 1 to about 8 carbonatoms, more preferably 1 to about 6 carbon atoms, even more preferably 1to about 3 carbon atoms. Methylsulfinyl (--S(O)CH₃) and ethylsulfinyl(--S(O)CH₂ CH₃) are particularly preferred R³, R⁴ and R⁵ alkylsulfinylgroups. Preferred substituted alkylsulfinyl groups includehaloalkylsulfinyl groups that contain one or more F, Cl, Br or I atoms,preferably one or more F atoms, and preferably 1 to about 3 carbonatoms, more preferably one or two carbon atoms. Specifically preferredgroups include fluoromethylsulfinyl, particularlytrifluoromethylsulfinyl (--S(O)CF₃), and fluoroethylsulfinyl such as2-trifluoroethylsulfinyl (--S(O)CH₂ CF₃) and pentafluoroethylsulfinyl(--S(O)CF₂ CF₃).

Preferred R³, R⁴ and R⁵ alkylsulfonyl ring substituents of compounds ofFormula II (as well as phenyl ring alkylsulfonyl groups of compounds ofFormulas IIa-IIc as specified below) have one or more sulfono (SO₂)groups, more typically one sulfono group, and from 1 to about 8 carbonatoms, still more preferably 1 to about 6 carbon atoms, even morepreferably 1 to about 3 carbon atoms. Methylsulfonyl (--S(O)₂ CH₃) andethylsulfonyl (--S(O)₂ CH₂ CH₃) are particularly preferred R³ and R⁴sulfonoalkyl groups. Preferred substituted alkylsulfonyl groups includehaloalkylsulfonyl groups that contain one or more F, Cl, Br or I atoms,preferably one or more F atoms, and preferably 1 to about 3 carbonatoms, more preferably one or two carbon atoms. Specifically preferredgroups include fluoromethylsulfonyl, particularlytrifluoromethylsulfonyl (--S(O)₂ CF₃), and fluoroethylsulfonyl such as2-trifluoroethylsulfonyl (--S(O)₂ CH₂ CF₃) and pentafluoroethylsulfonyl(--S(O)₂ CF₂ CF₃).

Particularly preferred R and R¹ groups include phenyl substituted atleast at the 2,5 ring positions. For example, preferred are thefollowing compounds of Formula Ia: ##STR4## wherein R and R² are thesame as defined above for Formula I; each R³, R⁴, R⁵, R^(3'), R^(4'),and R^(5') substituent is independently selected from the same group ofsubstituents as defined above for R³ --R⁵ for Formula I; m and n areeach independently an integer of from 0 to 3; and pharmaceuticallyacceptable salts thereof. Preferred compounds of

Formula Ia include those compounds where at least one of R and R² isother than heterocyclic aryl or carbocyclic aryl, e.g. where at leastone of R and R² is hydrogen or substituted or unsubstituted alkyl,particularly, substituted or unsubstituted alkyl having 1, 2, 3 or 4carbon atoms. Preferred values of m and n of Formula Ia are 0 and 1.

Also preferred are compounds of Formula IIa, defined the same as forFormula Ia above, but where each substituent, particularly the R³, R⁴,R⁵, R^(3'), R^(4'), and R^(5') substituents, may be independentlyalkylsulfinyl having from 1 to about 20 carbon atoms or alkylsulfonylhaving from 1 to about 20 carbon atoms. Preferred compounds of FormulaIIa include those compounds where at least one of R and R² is other thanheterocyclic aromatic or carbocyclic aryl, e.g. where at least one of Rand R² is hydrogen or substituted or unsubstituted alkyl, particularly,substituted or unsubstituted alkyl having 1, 2, 3 or 4 carbon atoms.Preferred values of m and n of Formula IIa are 0 and 1.

Further preferred compounds of Formula I include those compounds wherethe value n equals 1, particularly where n equals 1 and the phenyl ringis substituted by a R⁵ group at the 3- or 4-position, i.e. the phenylring is 2,3,5-substituted or 2,4,5-substituted.

Such compounds of Formula II are also preferred, i.e. compounds ofFormula II where the value n equals 1, particularly where n equals 1 andthe phenyl ring is substituted by a R⁵ group at the 3- or 4-position,i.e. the phenyl ring is 2,3,5-substituted or 2,4,5-substituted.

Especially preferred compounds of Formula I are those where n is equalto zero (i.e., the 3, 4 and 6 positions of the phenyl ring arehydrogen-substituted), specifically compounds of the following FormulaIb: ##STR5## where the groups R through R⁴ are the same as specifiedabove for Formula I; and pharmaceutically acceptable salts thereof.Particularly preferred compounds of Formula Ib include those compoundswhere R is substituted or unsubstituted heterocylic aryl or substitutedor unsubstituted carbocyclic aryl such as substituted or unsubstitutedphenyl or napthyl and where at least one of R¹ and R² is other thanheterocyclic aryl or carbocyclic aryl, e.g. where at least one of R¹ andR² is hydrogen or substituted or unsubstituted alkyl, particularlysubstituted or unsubstituted alkyl having 1, 2, 3 or 4 carbon atoms.

Also preferred are compounds of Formula IIb, defined the same as forFormula Ib above, but where each substituent, particularly the R³ and R⁴substituents, may be independently alkylsulfinyl having from 1 to about20 carbon atoms or alkylsulfonyl having from 1 to about 20 carbon atoms.Particularly preferred compounds of Formula IIb include those compoundswhere R is substituted or unsubstituted heterocylic aryl or substitutedor unsubstituted carbocyclic aryl such as substituted or unsubstitutedphenyl or napthyl and where at least one of R¹ and R² is other thanheterocyclic aryl or carbocyclic aryl, e.g. where at least one of R¹ andR² is hydrogen or substituted or unsubstituted alkyl, particularlysubstituted or unsubstituted alkyl having 1, 2, 3 or 4 carbon atoms.

A still further group of preferred compounds of the invention have, inaddition to a 2,5-substituted phenyl moiety, at least one guanidinesubstituent (i.e., R, R¹ or R₂ of Formulas I or II) that is a phenylgroup substituted at the 3-position, preferably without substitution atother ring positions. Particularly preferred are N-(3-substitutedphenyl)-N'-(2,5-disubstituted phenyl)guanidines of the following FormulaIc: ##STR6## wherein R and R² are the same as defined above for FormulaI; each R^(3'), R^(4'), R^(5') and R^(3") substituent is independentlyselected from the same group of substituents as defined above for R³, R⁴and R⁵ for Formula I; and n is an integer of from 0 to 3; andpharmaceutically salts of said compounds. Preferred compounds of FormulaIc include those compounds where at least one of R and R² is other thanheterocyclic aryl or carbocyclic aryl, e.g. where at least one of R andR² is hydrogen or substituted or unsubstituted alkyl, particularlysubstituted or unsubstituted alkyl having 1 to about 4 carbon atoms.Especially preferred are compounds of Formula Ic are those where one ofR and R² is hydrogen and the other is substituted or unsubstituted alkylhaving 1, 2, 3 or 4 carbon atoms, more preferably where R is methyl,ethyl or propyl and R² is hydrogen. Preferred values of n of Formula Icare 0 and 1.

Also preferred are compounds of Formula IIc, defined the same as forFormula Ic above, but where each substituent, particularly the R^(3'),R^(4'), R^(5') and R^(3") substituents, also may be independentlyalkylsulfinyl having from 1 to about 20 carbon atoms or alkylsulfonylhaving from 1 to about 20 carbon atoms. Preferred compounds of FormulaIIc include those compounds where at least one of R and R² is other thanheterocyclic aryl or carbocyclic aryl, e.g. where at least one of R andR² is hydrogen or substituted or unsubstituted alkyl, particularlysubstituted or unsubstituted alkyl having 1, 2, 3 or 4 carbon atoms.Especially preferred are compounds of Formula IIc are those where one ofR and R² is hydrogen and the other is substituted or unsubstituted alkylhaving 1 to about 4 carbon atoms, more preferably where R is methyl,ethyl or propyl and R² is hydrogen. Preferred values of n of Formula IIcare 0 and 1.

Preferred compounds of Formulas I and II exhibit high affinity to thePCP receptor. For at least some therapeutic applications, use ofcompounds of Formulas I or II that exhibit high affinity to both the PCPreceptor and the sigma receptor may be preferred. While not wishing tobe bound by theory, it is thought that an agent that has high affinityto both the PCP and sigma receptors can provide effective therapy forthe indications mentioned above without the risk of vacuolar injury asexhibited by some prior NMDA receptor antagonists. See, e.g., Olney etal., Science, 244:1360-1364 (1989).

Without wishing to be bound by theory, compounds of the invention thatcontain an alkylsulfinyl and/or alkylsulfonyl group, may be, in effect,"pro-drugs" wherein after administration of the compound to a subjectthe sulfinyl or sulfonyl group(s) are metabolized (reduced) in vivo tothe corresponding sulfide moiety. In particular, compounds of theinvention that have an aryl substituent that is ring-substituted by oneor more alkylsulfinyl and/or alkylsulfonyl group(s) may be effectivepro-drugs. Thus, preferred compounds of Formula II include thosecontaining a carbocyclic or heterocyclic group, such as a naphthyl orphenyl group, substituted by one or more alkylsulfinyl or alkylsulfonylgroups having from 1 to about 4 carbon atoms.

Specifically preferred compounds of the present invention include:

N-(3-ethylphenyl)-N,N'-dimethyl-N'-(2,5-dichlorophenyl)guanidine;

N-(3-ethylphenyl)-N-methyl-N'-(2,5-dichlorophenyl)guanidine;

N-(3-ethylphenyl)-N'-(2,5-dichlorophenyl)-N'-methylguanidine;

N-(3-ethylphenyl)-N'-(2,5-dichlorophenyl)guanidine;

N-(3-ethylphenyl)-N-methyl-N'-(2,5-dibromophenyl)guanidine;

N-(3-ethylphenyl)-N'-(2,5-dibromophenyl)-N'-methylguanidine;

N-(3-ethylphenyl)-N'-(2,5-dibromophenyl)guanidine;

N-(3-ethylphenyl)-N-methyl-N'-(2-chloro-5-trifluromethylphenyl)guanidine;

N-(3-ethylphenyl)-N'-(2-chloro-5-trifluoromethylphenyl)guanidine;

N-(3-ethylphenyl)-N,N'-dimethyl-N'-(2-bromo-5-trifluoromethylphenyl)guanidine;

N-(3-ethylphenyl)-N-methyl-N'-(2-bromo-5-trifluromethylphenyl)guanidine;

N-(3-ethylphenyl)-N'-(2-bromo-5-trifluoromethylphenyl)guanidine;

N-(3-ethylphenyl)-N-methyl-N'-(2-fluoro-5-trifluromethylphenyl)guanidine;

N-(3-ethylphenyl)-N'-(2-fluoro-5-trifluoromethylphenyl)guanidine;

N-(3-ethylphenyl)-N,N'-dimethyl-N'-(2-chloro-5-ethylphenyl)guanidine;

N-(3-ethylphenyl)-N-methyl-N'-(2-chloro-5-ethylphenyl)guanidine;

N-(3-ethylphenyl)-N'-(2-chloro-5-ethylphenyl)guanidine;

N-(3-ethylphenyl)-N,N'-dimethyl-N'-(2-bromo-5-ethylphenyl)guanidine;

N-(3-ethylphenyl)-N-methyl-N'-(2-bromo-5-ethylphenyl)guanidine;

N-(3-ethylphenyl)-N'-(2-bromo-5-ethylphenyl)guanidine;

N-(3-ethylphenyl)-N,N'-dimethyl-N'-(2-fluoro-5-ethylphenyl)guanidine;

N-(3-ethylphenyl)-N-methyl-N'-(2-fluoro-5-ethylphenyl)guanidine;

N-(3-ethylphenyl)-N'-(2-fluoro-5-ethyiphenyl)guanidine;

N-(3-ethylphenyl)-N,N'-dimethyl-N'-(2-chloro-5-methylphenyl)guanidine;

N-(3-ethylphenyl)-N-methyl-N'-(2-chloro-5-methylphenyl)guanidine;

N-(3-ethylphenyl)-N'-(2-chloro-5-ethylphenyl)guanidine;

N-(3-ethylphenyi)-N'-(2-chloro-5-methylphenyl)guanidine;

N-(3-ethylphenyl)-N-methyl-N'-(2-chloro-5-methylthio)guanidine;

N-(3-ethylphenyl)-N'-(2-chloro-5-methylthio)guanidine;

N-(1-naphthyl)-N'-(2-bromo-5-ethylphenyl)guanidine;

N-(1-naphthyl-N'-(2-fluoro-5-ethylphenyl)guanidine;

N-(1-naphthyl)-N'-(2,5-dichlorophenyl)guanidine;

N-(1-naphthyl)-N'-(2-fluoro-5-methylphenyl)guanidine;

N-(3-ethylphenyl)-N-methyl-N'-(2,4,5-trichlorophenyl)guanidine;

N-(3-ethylphenyl)-N'-(2,4,5-trichlorophenyl)guanidine;

N-(3-ethylphenyl)-N-methyl-N'-(2,3,5-trichlorophenyl)guanidine;

N-(3-ethylphenyl)-N'-(2,3,5-trichlorophenyl)guanidine;

N-(1-naphthyl)-N'-(2,4,5-trichlorophenyl)guanidine;

N-(1-naphthyl)-N'-(2,3,5-trichlorophenyl)guanidine;

N-(1-naphthyl)-N'-(2,5-dichlorophenyl)-N'-methylguanidine;

N-(1-naphthyl)-N'-(2-chloro-5-methylphenyl)guanidine;

N-(1-naphthyl)-N'-(2,5-dimethylphenyl)guanidine;

N-(1-naphthyl)-N'-(2,5-dibromophenyl)guanidine;

N-(1-naphthyl)-N'-(2-chloro-5-methylphenyl)-N'-methylguanidine;

N-(1-naphthyl)-N'-(2-5-dimethylphenyl)-N'-methylguanidine;

N-(1-naphthyl)-N'-(2,5-dibromophenyl)-N-methylguanidine;

N-(1-naphthyl)-N'-(2,5-dibromophenyl)-N'-methylguanidine;

N-(1-naphthyl)-N'-(2-chloro-5-thiomethylphenyl)guanidine;

N-(1-naphthyl)-N'-(2-fluoro-5-trifiuoromethylphenyl)guanidine;

N-(1-naphthyl)-N'-(2-chloro-5-trifluoromethylphenyl)guanidine;

N-(1-naphthyl)-N'-(2-bromo-5-trifluoromethylphenyl)guanidine;

N-(1-naphthyl)-N'-(2-thiomethyl-5-trifluoromethylphenyl)guanidine;

N-(1-naphthyl)-N'-(2-methoxy-5-methylphenyl)guanidine;

N-(1-naphthyl)-N'-(2-chloro-5-ethylphenyl)guanidine;

N-(1-naphthyl)-N'-(2-chloro-5-ethylphenyl)-N'-methylguanidine;

N-(1-naphthyl)-N'-methyl-N'-(2-chloro-5-thiomethylphenyl)guanidine;

N-(8-quinolinyl)-N'-(2-chloro-5-methylphenyl)guanidine;

N-(8-quinolinyl)-N'-(2-chloro-5-ethylphenyl)guanidine;

N-(8-quinolinyl)-N'-methyl-(2-chloro-5-ethylphenyl)guanidine;

N-(3-methylthiophenyl)-N-methyl-N'-(2-chloro-5-methylthiophenyl)guanidine;

N-(3-methylthiophenyl)-N'-methyl-N'-(2-chloro-5-methylthiophenyl)guanidine;

N-(3-methylthiophenyl)-N'-(2-chloro-5-methylthiophenyl)guanidine;

N-(3-methylthiophenyl)-N-methyl-N'-(2-chloro-5-ethylphenyl)guanidine;

N-(3-methylthiophenyl)-N'-methyl-N'-(2-chloro-5-ethylphenyl)guanidine;

N-(3-methylthiophenyl)-N'-(2-chloro-5-ethylphenyl)guanidine;

N-(3-methylthiophenyl)-N-methyl-N'-(2-bromo-5-ethylphenyl)guanidine;

N-(3-methylthiophenyl)-N'-methyl-N'-(2-bromo-5-ethylphenyl)guanidine;

N-(3-methylthiophenyl)-N'-(2-bromo-5-ethylphenyl)guanidine;

N-(3-methylthiophenyl-N-methyl-N'-(2,5-dichlorophenyl)guanidine;

N-(3-methylthiophenyl-N'-methyl-N'-(2,5-dichlorophenyl)guanidine;

N-(3-methylthiophenyl-N'-(2,5-dichlorophenyl)guanidine;

N-(3-methylthiophenyl)-N-methyl-N'-(2,5-dibromophenyl)guanidine;

N-(3-methylthiophenyl)-N'-methyl-N'-(2,5-dibromophenyl)guanidine;

N-(3-methylthiophenyl)-N'-(2,5-dibromophenyl)guanidine;

N-(3-trifluoromethylphenyl)-N-methyl-N'-(2-chloro-5-methylthiophenyl)guanidine;

N-(3-trifluoromethylphenyl)-N'-methyl-N'-(2-chloro-5-methylthiophenyl)guanidine;

N-(3-trifluoromethylphenyl)-N'-(2-chloro-5-methylthiophenyl)guanidine;

N-(3-trifluoromethylphenyl)-N-methyl-N'-(2-chloro-5-ethylphenyl)guanidine;

N-(3-trifluoromethylphenyl)-N'-methyl-N'-(2-chloro-5-ethylphenyl)guanidine;

N-(3-trifluoromethylphenyl)-N'-(2-chloro-5-ethylphenyl)guanidine;

N-(3-trifluoromethylphenyl)-N-methyl-N'-(2-bromo-5-ethylphenyl)guanidine;

N-(3-trifluoromethylphenyl)-N'-methyl-N'-(2-bromo-5-ethylphenyl)guanidine;

N-(3-trifluoromethylphenyl)-N'-(2-bromo-5-ethylphenyl)guanidine;

N-(3-trifluoromethylphenyl)-N-methyl-N'-(2,5-dichlorophenyl)guanidine;

N-(3-trifluoromethylphenyl)-N'-methyl-N'-(2,5-dichlorophenyl)guanidine;

N-(3-trifluoromethylphenyl)-N'-(2,5-dichlorophenyl)guanidine;

N-(3-trifluoromethylphenyl)-N-methyl-N'-(2,5-dibromophenyl)guanidine;

N-(3-trifluoromethylphenyl)-N'-methyl-N'-(2,5-dibromophenyl)guanidine;

N-(3-trifluoromethylphenyl)-N'-(2,5-dibromophenyl)guanidine;

N-(3-ethylphenyl)-N-methyl-N'-(2-bromo-5-methylthiophenyl)guanidine;

N-(3-ethylphenyl)-N'-methyl-N'-(2-bromo-5-methylthiophenyl)guanidine;

N-(3-ethylphenyl)-N'-(2-bromo-5-methylthiophenyl)guanidine;

N-(3-methylthiophenyl)-N-methyl-N'-(2-bromo-5-methylthiophenyl)guanidine;

N-(3-methylthiophenyl)-N'-methyl-N'-(2-bromo-5-methylthiophenyl)guanidine;

N-(3-methylthiophenyl)-N'-(2-bromo-5-methylthiophenyl)guanidine;

N-(3-methylthiophenyl)-N-methyl-N'-(2-bromo-5-ethylphenyl)guanidine;

N-(3-methylthiophenyl)-N'-methyl-N'-(2-bromo-5-ethylphenyl)guanidine;

N-(3-methylthiophenyl)-N'-(2-bromo-5-ethylphenyl)guanidine;

N-(3-trifluoromethylphenyl)-N-methyl-N'-(2-bromo-5-methylthiophenyl)guanidine;

N-(3-trifluoromethylphenyl)-N'-methyl-N'-(2-bromo-5-methylthiophenyl)guanidine;

N-(3-trifluoromethylphenyl)-N'-(2-bromo-5-methylthiophenyl)guanidine;

N-(3-bromophenyl)-N-methyl-N'-(2-chloro-5-methylthiophenyl)guanidine;

N-(3-bromophenyl)-N'-methyl-N'-(2-chloro-5-methylthiophenyl)guanidine;

N-(3-bromophenyl)-N'-(2-chloro-5-methylthiophenyl)guanidine;

N-(3-trifluoromethoxyphenyl)-N-methyl-N'-(2,5-dibromophenyl)guanidine;

N-(3-trifluoromethoxyphenyl)-N'-methyl-N'-(2,5-dibromophenyl)guanidine;

N-(3-trifluoromethoxyphenyl)-N'-(2,5-dibromophenyl)guanidine;

N-(3-trifluoromethoxyphenyl)-N-methyl-N'-(2-bromo-5-ethylphenyl)guanidine;

N-(3-trifluoromethoxyphenyl)-N'-methyl-N'-(2-bromo-5-5ethylphenyl)guanidine;

N-(3-trifluoromethoxyphenyl)-N'-(2-bromo-5-ethylphenyl)guanidine;

N-(3-methylsulfonylphenyl)-N-methyl-N'-(2,5-dibromophenyl)guanidine;

N-(3-methylsulfonylphenyl)-N'-methyl-N'-(2,5-dibromophenyl)guanidine;

N-(3-methylsulfonylphenyl)-N'-(2,5-dibromophenyl)guanidine;

N-(3-methylsulfinylphenyl)-N-methyl-N'-(2,5-dibromophenyl)guanidine;

N-(3-methylsulfinylphenyl)-N'-methyl-N'-(2,5-dibromophenyl)guanidine;

N-(3-methylsulfinylphenyl)-N'-(2,5-dibromophenyl)guanidine;

N-(3-iodophenyl)-N-methyl-N'-(2-chloro-5-methylthiophenyl)guanidine;

N-(3-iodophenyl)-N'-methyl-N'-(2-chloro-5-methylthiophenyl)guanidine;

N-(3-iodophenyl)-N'-(2-chloro-5-methylthiophenyl)guanidine;

N-(3-iodophenyl)-N-methyl-N'-(2-chloro-5-ethylphenyl)guanidine;

N-(3-iodophenyl)-N'-methyl-N'-(2-chloro-5-ethylphenyl)guanidine;

N-(3-iodophenyl)-N'-(2-chloro-5-ethylphenyl)guanidine;

N-(3-ethylphenyl)-N'-(2-chloro-5-ethylthiophenyl)guanidine;

N-(3-ethylphenyl)-N-methyl-N'-(2-chloro-5-ethylthiophenyl)guanidine;

N-(3-ethylphenyl)-N'-methyl-N'-(2-chloro-5-ethylthiophenyl)guanidine;

N-(3-ethylphenyl)-N,N'-dimethyl-N'-(2-chloro-5-ethylthiophenyl)guanidine;

N-(3-ethylphenyl)-N'-(2-bromo-5-ethylthiophenyl)guanidine;

N-(3-ethylphenyl)-N-methyl-N'-(2-bromo-5-ethylthiophenyl)guanidine;

N-(3-ethylphenyl)-N'-methyl-N'-(2-bromo-5-ethylthiophenyl)guanidine;

N-(3-ethylphenyl)-N,N'-dimethyl-N'-(2-bromo-5-ethylthiophenyl)guanidine;

N-(3-methylthiophenyl)-N'-(2-chloro-5-ethylthiophenyl)guanidine;

N-(3-methylthiophenyl)-N-methyl-N'-(2-chloro-5-ethylthiophenyl)guanidine;

N-(3-methylthiophenyl)-N'-methyl-N'-(2-chloro-5-ethylthiophenyl)guanidine;

N-(3-methylthiophenyl)-N,N'-dimethyl-N'-(2-chloro-5-ethylthiophenyl)guanidine;

N-(3-methylthiophenyl)-N'-(2-bromo-5-ethylthiophenyl)guanidine;

N-(3-methylthiophenyl)-N-methyl-N'-(2-bromo-5-ethylthiophenyl)guanidine;

N-(3-methylthiophenyl)-N'-methyl-N'-(2-bromo-5-ethylthiophenyl)guanidine;

N-(3-methylthiophenyl)-N,N'-dimethyl-N'-(2-bromo-5-ethylthiophenyl)guanidine;

N-(3-trifluoromethylphenyl)-N'-(2-chloro-5-ethylthiophenyl) guanidine;

N-(3-trifluoromethylphenyl)-N-methyl-N'-(2-chloro-5-ethylthiophenyl)guanidine;

N-(3-trifluoromethylphenyl)-N'-methyl-N'-(2-chloro-5-ethylthiophenyl)guanidine;

N-(3-trifluoromethylphenyl)-N,N'-dimethyl-N'-(2-chloro-5-ethylthiophenyl)guanidine;

N-(3-trifluoromethylphenyl)-N'-(2-bromo-5-ethylthiophenyl)guanidine;

N-(3-trifluoromethylphenyl)-N-methyl-N'-(2-bromo-5-ethylthiophenyl)guanidine;

N-(3-trifluoromethylphenyl)-N'-methyl-N'-(2-bromo-5-ethylthiophenyl)guanidine;

N-(3-trifluoromethylphenyl)-N,N'-dimethyl-N'-(2-bromo-5-ethylthiophenyl)guanidine;

N-(3-ethylphenyl)-N'-(2-chloro-5-trifluoromethylthiophenyl)guanidine;

N-(3-ethylphenyl)-N-methyl-N'-(2-chloro-5-trifluoromethylthiophenyl)guanidine;

N-(3-ethylphenyl)-N'-methyl-N'-(2-chloro-5-trifluoromethylthiophenyl)guanidine;

N-(3-ethylphenyl)-N,N'-dimethyl-N'-(2-chloro-5-trifluoromethylthiophenyl)guanidine;

N-(3-ethylphenyl)-N'-(2-bromo-5-trifluoromethylthiophenyl)guanidine;

N-(3-ethylphenyl)-N-methyl-N'-(2-bromo-5-trifluoromethylthiophenyl)guanidine;

N-(3-ethylphenyl)-N'-methyl-N'-(2-bromo-5-trifluoromethylthiophenyl)guanidine;

N-(3-ethylphenyl)-N,N'-dimethyl-N'-(2-bromo-5-trifluoromethylthiophenyl)guanidine;

N-(3-methylthiophenyl)-N'-(2-chloro-5-trifluoromethylthiophenyl)guanidine;

N-(3-methylthiophenyl)-N-methyl-N'-(2-chloro-5-trifluoromethylthiophenyl)guanidine;

N-(3-methylthiophenyl)-N'-methyl-N'-(2-chloro-5-trifluoromethylthiophenyl)guanidine;

N-(3-methylthiophenyl)-N,N'-dimethyl-N'-(2-chloro-5-trifluoromethylthiophenyl)guanidine;

N-(3-methylthiophenyl)-N'-(2-bromo-5-trifluoromethylthiophenyl)guanidine;

N-(3-methylthiophenyl)-N-methyl-N'-(2-bromo-5-trifluoromethylthiophenyl)guanidine;

N-(3-methylthiophenyl)-N'-methyl-N'-(2-bromo-5-trifluoromethylthiophenyl)guanidine;

N-(3-methylthiophenyl)-N,N'-dimethyl-N'-(2-bromo-5-trifluoromethylthiophenyl)guanidine;

N-(3-trifluoromethylphenyl)-N'-(2-chloro-5-trifluoromethylthiophenyl)guanidine;

N-(3-trifluoromethylphenyl)-N-methyl-N'-(2-chloro-5-trifluoromethylthiophenyl)guanidine;

N-(3-trifluoromethylphenyl)-N'-methyl-N'-(2-chloro-5-trifluoromethylthiophenyl)guanidine;

N-(3-trifluoromethylphenyl)-N,N'-dimethyl-N'-(2-chloro-5-trifluoromethylthiophenyl)guanidine;

N-(3-trifluoromethylphenyl)-N'-(2-bromo-5-trifluoromethylthiophenyl)guanidine;

N-(3-trifluoromethylphenyl)-N-methyl-N'-(2-bromo-5-trifluoromethylthiophenyl)guanidine;

N-(3-trifluoromethylphenyl)-N'-methyl-N'-(2-bromo-5-trifluoromethylthiophenyl)guanidine;

N-(3-trifluoromethylphenyl)-N,N'-dimethyl-N'-(2-bromo-5-trifluoromethylthiophenyl)guanidine;

N-(1-naphthyl)-N'-(2-chloro-5-methylthiophenyl)guanidine;

N-(1-naphthyl)-N'-(2-iodo-5-methylthiophenyl)guanidine;

N-(1-naphthyl)-N'-(2-bromo-5-methylthiophenyl)guanidine; andpharmaceutically acceptable salts of said compounds.

Also specifically preferred are compounds specifically identified 25above and having one or more additional guanidine substituents (i.e., R,R¹ or R² substituents of Formulas I or II) that are other than hydrogen,particularly one or more additional substituents that are substituted orunsubstituted alkyl, especially unsubstituted methyl, ethyl, propyl,butyl, pentyl or hexyl, more preferably unsubstituted methyl, ethyl orpropyl. For example, tetra-substituted compounds are particularlypreferred such as di-alkyl-, di-aryl-substituted compounds such asN-(3-ethylphenyl)-N,N'-dimethyl-N'-(2,5-dibromophenyl)guanidine,N-(3-ethylphenyl)-N,N'-dimethyl-N'-(2-chloro-5-trifluromethylphenyl)guanidine,and the like.

In a further aspect, the invention provides compounds of Formula II',which Formula II' is defined the same as Formula II above but where eachof the substituents R³, R⁴ and each R⁵ also may be independently nitro,cyano, substituted or unsubstituted alkanoyl or substituted orunsubstituted carboxyl. Suitable and preferred substituents of compoundsof Formula II as disclosed herein are also suitable and preferredsubstituents of Formula II'. Suitable alkanoyl groups of Formula II'have 1 to about 8 carbon atoms, more preferably 1 to about 4 carbonatoms. Acyl is a particularly suitable alkanoyl group. Carboxyl groupsof Formula II' include acid and ester groups of the formula --(CH₂)_(n)COOY where n is an integer equal to 0 to about 8, more preferably 1, 2,3 or 4, and Y is hydrogen or substituted or unsubstituted alkyl,preferably have 1 to about 6 carbon atoms, or 1 to about 3 carbon atoms.Compounds of Formula II' can be prepared as disclosed herein forsynthesis of compounds of Formulas I and II. The invention also includesuse of compounds of Formula II' for the methods of treatment disclosedherein, in the same manner as described for Formulas I and II.

Compounds of Formulas I and II can be readily prepared by the reactionof an amine, typically an amine salt such as an amine hydrochloride,with a preformed alkyl or aryl cyanamide (see S. R. Safer, et al., J.Org. Chem., 13:924 (1948)) or the corresponding N-substituted alkyl oraryl cyanamide. This is a particularly suitable method for producingN,N'-diaryl-N'-alkyl guanidines in which the substituents are notidentical. For a synthesis of asymmetrical guanidines, see G. J. Durant,et al., J. Med. Chem., 28:1414 (1985), and C. A. Maryanoff, et al., J.Org. Chem., 51:1882 (1986), incorporated by reference herein. Foradditional discussion of guanidine synthesis, see PCT application WO91/12797 and U.S. Pat. Nos. 5,093,525, 5,262,568 and 5,265,568, allincorporated by reference herein. See also H. W. J. Cressman, Org. Syn.Coll., 3:608-609 (1955); M. P. Kavanaugh, et al., Proc. Natl. Acad. Sci.USA, 85:2844-2848 (1988); and E. Weber, et al., Proc. Natl. Acad. Sci.USA, 83:8784-8788 (1 986), all incorporated herein by reference.

More particularly, compounds of Formulas I and II can be preparedsuitably by reaction of an appropriate amine salt such an aminehydrochloride with a slight molar excess (e.g., ca. 1.1 molarequivalent) of a substituted cyanamide in a suitable solvent such astoluene or chlorobenzene under an inert atmosphere such as argon ornitrogen. The reaction solution is then heated from about 110° to 120°C. for 2 to about 16 hours until reaction completion, e.g. as indicatedby thin layer chromatography. The reaction solution is then cooled toroom temperature, and then preferably diluted with a solvent such asabsolute alcohol. The solvent is then removed under reduced pressure toprovide the desired substituted guanidine. The crude product then can bepurified by recrystallization and/or flash chromatography, e.g. byelution on silica gel (60-200 mesh, 50× w/w) with 5-25% methanol inethyl acetate. Suitable recrystallization solvents include anethanol/ethyl acetate mixture or an ethanol/ether mixture. The cyanamideand amine reagents with appropriate substituents (i.e., R, R¹, R² andR³,R⁴,R⁵ -substituted phenyl substituents), are commercially availableor can be readily prepared by known procedures. For example, thecyanamide starting material can be synthesized from the correspondinglysubstituted amine by treatment with cyanogen bromide (BrCN) in suitablesolvent such as dry ethyl ether. The amine hydrochloride can be obtainedby treatment of an appropriate amine with an excess of HCl. For example,a 2,5-substituted aniline hydrochloride salt can be prepared by addingmethanolic HCl to a cooled solution of the substituted aniline and thenstirring at room temperature for about 30 minutes. Analkylsulfinyl-substituted or alkylsulfonyl-substituted reagent, that canprovide correspondingly substituted compounds of the invention asdescribed above, can be provided by oxidation (e.g., H₂ O₂) ofalkylthio-substituted reagents. See, for instance, Example 5 whichfollows.

As discussed above, the present invention includes methods for treatingor preventing certain neurological disorders, including the consequencesof stroke or traumatic brain injury, epilepsy or neurodegenerativediseases comprising the administration of an effective amount of one ormore guanidines of Formulas I or II to a subject including a mammal,particularly a human, in need of such treatment. In particular, theinvention provides methods for treatment and/or prophylaxis of nervecell death resulting e.g. from hypoxia, hypoglycemia, brain or spinalcord ischemia, brain or spinal cord trauma, stroke, heart attack ordrowning. Typical candidates for treatment include e.g. heart attack,stroke, brain or spinal cord injury patients, patients undergoing majorsurgery such as heart surgery where brain ischemia is a potentialcomplication and patients such as divers suffering from decompressionsickness due to gas emboli in the blood stream.

In particular, the invention provides methods for treatment whichcomprise administration of one or more compounds of the invention to apatient that is undergoing surgery or other procedure where brain orspinal cord ischemia is a potential risk. For example, carotidendarterectomy is a surgical procedure employed to correctatherosclerosis of the carotid arteries. Major risks associated with theprocedure include intraoperative embolization and the danger ofhypertension in the brain following increased cerebral blood flow, whichmay result in aneurism or hemorrhage. Thus, an effective amount of oneor more compounds of the present invention could be administeredpre-operatively or peri-operatively to reduce such risks associated withcarotid endarterectomy.

The present invention further includes methods for prophylaxis againstneurological deficits resulting from coronary artery bypass grafts andaortic valve replacement surgery. Those methods will compriseadministering to a patient undergoing such surgical procedures aneffective amount of one or more compounds of the invention, typicallyeither pre-operatively or peri-operatively.

The present invention also provides methods for prophylaxis againstneurological injury for patients undergoing myocardial infarction, aprocedure that can result in ischemic insult to the patient. Suchmethods will comprise administering to a patient undergoing suchsurgical procedure an effective amount of one or more compounds of theinvention, typically either pre-operatively or peri-operatively.

Also provided are methods for treating or preventing neuropathic painsuch as may experienced by cancer patients, persons having diabetes,amputees and other persons who may experience neuropathic pain. Thesemethods for treatment comprise administration of an effective amount ofone or more compounds of Formulas I or II to a patient in need of suchtreatment.

Further provided are methods of ameliorating the neurotoxic effectinduced by glutamate interacting with the NMDA receptor of a nerve cell,comprising administering to a subject, such as a mammal, particularly ahuman, exhibiting symptoms of or susceptible to such neurotoxic effect,one or more compounds of Formulas I or II in an amount effective toameliorate the neurotoxic effect.

This invention also provides methods of inhibiting NMDA receptor-ionchannel related neurotoxicity comprising administering to a subject inneed thereof such as a mammal, particularly a human, one or morecompounds of Formulas I or II in an amount effective to inhibit orprevent the neurotoxicity.

The invention further provides a method of treating Korsakoff's disease,a chronic alcoholism-induced condition, comprising administering to asubject including a mammal, particularly a human, one or more compoundsof Formula I or Formula II in an amount effective to treat the disease.Pretreatment of animals with the NMDA antagonist MK-801 (Merck Index,monograph 3392, 11th ed., 1989) markedly attenuates the extent of cellloss, hemorrhages and amino acid changes in a rat model of Korsakoff'sdisease. See P. J. Langlais, et al., Soc. Neurosci. Abstr., 14:774(1988). Therefore, compounds of the present invention have utility forthe attenuation of cell loss, hemorrhages and amino acid changesassociated with Korsakoff's disease.

The invention also provides methods for determining binding activity ofcompounds of the invention, e.g. binding activity to NMDA receptors, aswell as in vitro and in vivo binding activity diagnostic methods usingone or more radiolabelled compounds of Formula I or Formula II, e.g., acompound of the invention that is labeled with ¹²⁵ I, tritium, ³² P, ⁹⁹Tc, or the like, preferably ¹²⁵ I. For instance, a compound of theinvention having a phenyl substituent that is ring substituted with oneor more ¹²⁵ I groups can be administered to a mammal and the subjectthen scanned for binding of the compound to NMDA receptors.Specifically, single photon emission computed tomography ("SPECT") canbe employed to detect such binding. Such an analysis of the mammal coulde.g. aid in the diagnosis and treatment of acute cerebral ischemia.

Accordingly, the invention includes compounds of Formula I or II thatcontain a radiolabel such as ¹²⁵ I, tritium, ³² P, ⁹⁹ Tc, or the like,preferably ¹²⁵ I. Such radiolabelled compounds can be suitably preparedby procedures known in the synthesis art. For example, a compound of theinvention having an aromatic group, such as phenyl, that has a bromo orchloro ring substituent can be employed in an exchange labeling reactionto provide the corresponding compound having an ¹²⁵ I ring substituent.

Certain pharmacological activity of compounds of Formulas I and II canbe determined by, e.g., a method involving: (a) determining the bindingaffinity with respect to the PCP receptor by competitive displacement oftritiated MK-801; (b) in vitro cytotoxicity studies measuring theability of the compound to prevent nerve cell death caused by exposureto glutamate; and (c) determination of in vivo neuroprotective abilityusing animal models.

Evaluation of the binding activity of compounds of Formulas I and IIwith respect to the PCP receptor is suitably performed using radioligandbinding assays. The compounds are tested to determine their ability todisplace tritiated MK-801 which is used to label PCP receptors.Evaluating the competitive displacement binding data, the preferredcompounds are those which exhibit a high affinity (i.e., low IC₅₀ value)for the PCP receptors. Under such PCP binding activity studies, an IC₅₀value of at most about 1 μM, preferably at most about 0.5 μM, indicatesa high binding affinity.

As discussed above, under sigma binding studies an IC₅₀ value of lessthan 1 μM indicates a high binding affinity of a compound to the sigmareceptor. The sigma receptor binding assay, preferably against ³ H-DTG,may be performed as disclosed by E. Weber, et al., Proc. Natl. Acad. Sci(USA), 83:8784-8788 (1986), which is incorporated by reference herein.

Compounds of Formulas I and II may be used in therapy in conjunctionwith other medicaments. For example, for treatment of a stroke victim,one or more compounds of Formulas I or II may be suitably administeredtogether with a pharmaceutical targeted for interaction in the bloodclotting mechanism such as streptokinase, tPA, urokinase and otheragents that lyse clots.

As discussed above, preferred guanidines of Formulas I and II exhibithigh affinity for the PCP receptor. Thus, in addition to the treatmentof neurodegeneration and related conditions discussed above, theguanidines of the present invention may also be used as apharmacological tool in an animal model for the screening of potentialPCP receptor ligands.

The compounds of this invention can be administered intranasally, orallyor by injection, e.g., intramuscular, intraperitoneal, subcutaneous orintravenous injection, or by transdermal, intraocular or enteral means.The optimal dose can be determined by conventional means. Guanidines ofthe present invention are suitably administered to a subject in theprotonated and water-soluble form, e.g., as a pharmaceuticallyacceptable salt of an organic or inorganic acid, e.g., hydrochloride,sulfate, hemi-sulfate, phosphate, nitrate, acetate, oxalate, citrate,maleate, etc.

The compounds of this invention can be employed, either alone or incombination with one or more other therapeutic agents as discussedabove, as a pharmaceutical composition in mixture with conventionalexcipient, i.e., pharmaceutically acceptable organic or inorganiccarrier substances suitable for parenteral, enteral or intranasalapplication which do not deleteriously react with the active compoundsand are not deleterious to the recipient thereof. Suitablepharmaceutically acceptable carriers include but are not limited towater, salt solutions, alcohol, vegetable oils, polyethylene glycols,gelatin, lactose, amylose, magnesium stearate, talc, silicic acid,viscous paraffin, perfume oil, fatty acid monoglycerides anddiglycerides, petroethral fatty acid esters, hydroxymethyl-cellulose,polyvinylpyrrolidone, etc. The pharmaceutical preparations can besterilized and if desired mixed with auxiliary agents, e.g., lubricants,preservatives, stabilizers, wetting agents, emulsifiers, salts forinfluencing osmotic pressure, buffers, colorings, flavorings and/oraromatic substances and the like which do not deleteriously react withthe active compounds.

For parenteral application, particularly suitable are solutions,preferably oily or aqueous solutions as well as suspensions, emulsions,or implants, including suppositories. Ampules are convenient unitdosages.

For enteral application, particularly suitable are tablets, dragees orcapsules having talc and/or carbohydrate carrier binder or the like, thecarrier preferably being lactose and/or corn starch and/or potatostarch. A syrup, elixir or the like can be used wherein a sweetenedvehicle is employed. Sustained release compositions can be formulatedincluding those wherein the active component is protected withdifferentially degradable coatings, e.g., by microencapsulation,multiple coatings, etc.

Intravenous or parenteral administration, e.g., sub-cutaneous,intraperitoneal or intramuscular administration are preferred. Thecompounds of this invention are particularly valuable in the treatmentof mammalian subjects, e.g., humans, wherein the pathophysiology of thedisease involves excessive excitation of nerve cells by agonists of theNMDA receptor. Typically, such subjects include those afflicted withneurodegenerative diseases such as Parkinson's disease, Huntington'sdisease, Amyotrophic Lateral Sclerosis, Alzheimer's disease, Down'sSyndrome and Korsakoff's disease. Also suitable for treatment are thosesubjects suffering from or likely to suffer from nervous systemdysfunctions resulting from, for example, epilepsy or nerve celldegeneration which is the result of hypoxia, hypoglycemia, brain orspinal chord ischemia or brain or spinal chord trauma. As discussedabove, typical candidates for treatment include heart attack, stroke,brain or spinal cord injury patients, patients undergoing major surgerywhere brain or spinal cord ischemia is a potential complication andpatients such as divers suffering from decompression sickness due to gasemboli in the blood stream.

It will be appreciated that the actual preferred amounts of activecompounds used in a given therapy will vary according to the specificcompound being utilized, the particular compositions formulated, themode of application, the particular site of administration, etc. Optimaladministration rates for a given protocol of administration can bereadily ascertained by those skilled in the art using conventionaldosage determination tests conducted with regard to the foregoingguidelines. In general, a suitable effective dose of one or morecompounds of Formula I or Formula II, particularly when using the morepotent compound(s) of Formulas I or II, will be in the range of from0.01 to 100 milligrams per kilogram of bodyweight of recipient per day,preferably in the range of from 0.01 to 20 milligrams per kilogrambodyweight of recipient per day, more preferably in the range of 0.05 to4 milligrams per kilogram bodyweight of recipient per day. The desireddose is suitably administered once daily, or several sub-doses, e.g. 2to 4 sub-doses, are administered at appropriate intervals through theday, or other appropriate schedule. Such sub-doses may be administeredas unit dosage forms, e.g., containing from 0.05 to 10 milligrams ofcompound(s) of Formula I or II per unit dosage, preferably from 0.2 to 2milligrams per unit dosage.

As with prior guanidines such as those reported in U.S. Pat. No.1,411,713, the guanidines of the present invention should have utilityas rubber accelerators.

The entire text of all applications, patents and publications citedabove and below are incorporated by reference herein.

The following non-limiting examples are illustrative of the invention.

GENERAL COMMENTS

In the following examples, melting points (mp) were determined in opencapillary tubes on a Thomas-Hoover apparatus (compounds melting <230°C.) and are uncorrected. The NMR spectra of all compounds were recordedon a General Electric QE-300 or Bruker 300, and chemical shifts arereported in ppm relative to the residual signal of the deuteratedsolvent (CHCl₃, 7.26 ppm; HCD₂ OD, 3.30 ppm; TMS, 0.00 ppm). IR spectrawere recorded on a Nicolet 5DXB FT-IR, or a Perkin-Elmer model 1420 inCHCl₃ or neat. IR and NMR spectra of all compounds are consistent withtheir assigned structures. Elemental analyses were performed by M-H-WLaboratories (Phoenix, Ariz.), or Galbraith Laboratories (Knoxville,Tenn.). 1-Naphthylamine, cyanogen bromide, 3-ethylaniline andchlorobenzene were obtained from Aldrich Chemical Company, and were usedas received. All other solvents were reagent grade. 1-Naphthyl cyanamidethat can be used to prepare compounds of Examples 27-46 and 51 issuitably prepared by the following procedure. To a solution of 20.0 g(140 mMol) 1-naphthylamine in ether at 0° C. was added by cannulation asolution of 17.5 mL (87.5 mMol) BrCN (5.0 M in CH₃ CN; Aldrich). After0.5 hours the cooling bath was removed and the mixture was stirred atroom temperature overnight (14 hours). A crystalline precipitate of theamine•HBr was formed, which was filtered off under suction, and washedwith ethyl acetate (15 mL×3). The filtrate was concentrated in vacuo toprovide 12.5 g of a purple colored solid of the crude cyanamide, whoseTLC showed the presence of minor amounts of the hydrobromide amine salt.The crude solid was stirred with water (200 mL) for 1 hour, after whichfiltration under suction left a pinkish solid which was dried in avacuum oven overnight to afford 9.2 g, (78.3%) of the pure 1-naphthylcyanamide.

EXAMPLE 1

Preparation ofN-(3-ethylphenyl)-N-methyl-N'-2,5-dichlorophenyl)guanidine hydrochloride(Formula I: hydrochloride salt of R=3-ethylphenyl, R¹ =CH₃, R² =H, R³=R⁴ ═Cl, n=0).

Part 1: Preparation of N-(3-ethylphenyl)-N-methylcyanamide

Step A: 3-ethylphenylcyanamide

A solution of cyanogen bromide (11.36 g, 107 mmol) in anhydrousdiethylether (50 mL) was added slowly to a stirred solution of3-ethylaniline (20.8 g, 171 mmol) in diethylether at 4° C. After theaddition, the reaction mixture was stirred at 24° C. for 12 hours and itbecame a brown solution with a white precipitate. The precipitate wasfiltered off; the filtrate was washed with aqueous HCl (1N, 3×150 mL)and brine (60 mL). Then the etherate solution was dried over MgSO₄,filtered, and concentrated to yield a thick liquid. The crude productwas further purified by chromatography (SiO₂, hexanes, hexanes/CH₂ Cl₂,CH₂ Cl₂) to afford 3-ethylphenylcyanamide (11.6 g, 76% in yield) as aliquid.

Step B: N-(3-ethylphenyl)-N-methylcyanamide

A suspension of 3-ethylphenylcyanamide (4.65 g, 31.8 mmol) and sodiumhydride (2.55 g of 80% NaH in mineral oil suspension, 63.6 mmol of NaH)in dried THF was heated at reflux for 3 hours. The reaction mixture wascooled in an ice bath and methyl iodide (11.28 g, 79.5 mmol) was addeddropwise with stirring to the mixture. The reaction mixture was thenallowed to stir for 15 hours, followed by the successive addition ofMeOH (10 mL). The reaction mixture was then concentrated to dryness togive the crude product. Distilled water (40 mL) was added to this crudeproduct and the aqueous mixture was extracted with CH₂ Cl₂ (4×40 mL).The combined organic extracts were washed with water (3×30 mL) and thendried over MgSO₄. The solvent was removed to afford the crude product asan amber syrup. Flash chromatography (SiO₂, CH₂ Cl₂) of the crudeproduct afforded 4.2 g (75% yield) of the desired product.

Part 2: Preparation of 2,5-Dichloroaniline Hydrochloride

To a solution of 2,5-dichloroaniline (Aldrich, 1.5 g, 9 mmol) inmethanol (10 mL) was added methanolic HCl (1M, 30 mL) at 4° C., then thereaction mixture was stirred at 25° C. for 30 minutes. The resultingsolution was then evaporated and dried under vacuum to afford 1.6 g of2,5-dichloroaniline hydrochloride (88% yield).

Part 3: Guanidine Synthesis

A mixture of N-(3-ethylphenyl)-N-methylcyanamide (520 mg, 3.3 mmol),2,5-dichloroaniline hydrochloride (600 mg, 3 mmol), and chlorobenzene (2mL) were combined in a dry round bottom flask equipped with a watercooled condenser under nitrogen and placed in a preheated oil bath(150-160° C.). The reaction mixture was heated for 4 hours. Aftercooling, the crude reaction product was purified by crystallization fromchlorobenzene/diethylether. The resulting crystals were collected byfiltration, washed with diethylether, and dried in a vacuum oven (40°C., 15 hours) to yield the title compound,N-(3-ethylphenyl)-N-methyl-N'-(2,5-dichlorophenyl)guanidinehydrochloride, as a white solid (760 mg, 72% yield).

TLC: R_(f) =0.45 (10% MeOH/CH₂ Cl₂); mp: 162-163° C.; ¹ H NMR (CD₃ OD):δ 7.53-7.23 (m, 7H, Ar--H), 3.48 (s, 3H, CH₃), 2.70 (q, J=7.6 Hz, 2H,CH₂), 1.26 (t, J=7.6 Hz, 3H, CH₃); MS(EI): m/e 322 (M⁺ for the freebase); Anal.: C₁₆ H₁₇ Cl₂ N₃.HCl; Calcd. (%): C: 53.57, H: 5.05, N:11.71; Found (%): C: 53.66, H: 5.20, N: 11.71.

EXAMPLE 2

Preparation ofN-(3-ethylphenyl)-N-methyl-N'-(2,5-dibromophenyl)guanidine hydrochloride(Formula I: hydrochloride salt of R=3-ethylphenyl, R¹ =CH₃, R₂ =H, R₃=R₄ ═Br, n=0).

Part 1: Preparation of 2,5-dibromoaniline hydrochloride

To a solution of 2,5-dibromoaniline (Aldrich, 1.5 g, 6 mmol) in methanol(5 mL) was added methanolic HCl (1M, 30 mL) at 4° C., then the reactionmixture was stirred at 25° C. for 30 minutes. The reaction mixturebecame a light brown solution with a white precipitate. The precipitatewas collected by filtration, washed with diethylether (2 mL), and driedunder vacuum to afford 1.6 g of 2,5-dibromoaniline hydrochloride (93%yield).

Part 2: Guanidine Synthesis

A mixture of N-(3-ethylphenyl)-N-methylcyanamide (520 mg, 3.3 mmol),2,5-dibromoaniline hydrochloride (861 mg, 3 mmol), and chlorobenzene (2mL) were combined in a dry round bottom flask equipped with water cooledcondenser under nitrogen and placed in a preheated oil bath (150-160°C.). The reaction mixture was heated for 3 hours. After cooling, thecrude reaction product was purified by crystallization fromchlorobenzene/diethylether. The resulting crystals were collected byfiltration, washed with diethylether, and dried in a vacuum oven (40°C., 15 hours) to yield the title compound,N-(3-ethylphenyl)-N-methyl-N'-(2,5-dibromophenyl)guanidinehydrochloride, as a white solid (780 mg, 59% yield).

TLC: R_(f) =0.5 (10% MeOH/CH₂ Cl₂); mp: 217-218° C.; ¹ H NMR (CD₃ OD): δ7.56-7.20 (m, 7H, Ar--H), 3.41 (s, 3H, CH₃), 2.62 (q, J=7.7 Hz, 2H,CH₂), 1.18 (t, J=7.7 Hz, 3H, CH₃); MS(EI): m/e 411 (M⁺ for the freebase); Anal.: C₁₆ H₁₇ Br₂ N₃.HCl; Calcd. (%): C: 42.93, H: 4.05, N:9.39; Found (%): C: 42.90, H: 4.01, N: 9.13.

EXAMPLE 3

Preparation of N-(3-ethylphenyl)-N'-(2,5-dichlorophenyl)guanidinemesylate (Formula I: mesylate of R=3-ethylphenyl, R¹ =R² ═H, R³ =R⁴ ═Cl,n=0).

Part 1: Preparation of 2,5-dichlorophenylcyanamide

To a heterogeneous slurry of 2,5-dichloroaniline (3.0 g, 18.5 mmol) in60 mL of water at 4° C. was added solid BrCN (1.22 g, 11.3 mmol) slowly.After 5 minutes the cooling bath was removed and the heterogeneousreaction mixture was stirred at room temperature for 24 hours to yieldthe product in water suspension. The product was collected byfiltration, washed with water (100 mL), and dried under vacuum to yieldthe pure product (2 g, 60% yield).

Part 2: Preparation of 3-ethylaniline mesylate

To a solution of 3-ethylaniline (Aldrich, 4.84 g, 40 mmol) in methanol(10 mL) was added methanesulfonic acid (4.4 g, 45 mmol) at 4° C., thenthe reaction mixture was stirred at 25° C. for 30 minutes to yield asolution with white precipitates. The precipitates were collected byfiltration, washed with ether, and dried under vacuum to afford 7.7 g of3-ethylaniline mesylate (7.7 g, 91% yield).

Part 3: Guanidine Synthesis

A mixture of 2,5-dichlorophenylcyanamide (1.02 g, 5.5 mmol),3-ethylaniline mesylate (1.1 g, 5 mmol), and chlorobenzene (15 mL) werecombined in a dry round bottom flask equipped with a water cooledcondenser under nitrogen and placed in a preheated oil bath (150-160°C.). The reaction mixture was heated for 2 hours. After cooling, thecrude reaction product was purified by crystallization fromchlorobenzene/diethylether. The resulting crystals were collected byfiltration, washed with diethylether, and dried in a vacuum oven (40°C., 15 hours) to yield the title compound,N-(3-ethylphenyl)-N'-(2,5-dichlorophenyl)guanidine mesylate, as a whitesolid (1.5 g, 75% yield).

TLC: R_(f) =0.4 (10% MeOH/CH₂ Cl₂); mp: 220-221° C.; ¹ H NMR (300 MHz,CD₃ OD): δ 7.58-7.17 (m, 7H, Ar--H), 2.68 (s, 3H, SO₃ CH₃), 2.68 (m, 2H,CH₃), 1.24 (t, J=7.6 Hz, CH₃); Anal: C₁₆ H₁₉ Cl₂ N₃ O₃ ; Calcd. (%): C:47.83, H: 4.74, N: 10.39; Found (%): C: 47.44, H: 4.64, N: 10.27.

EXAMPLE 4

Preparation of N-(3-ethylphenyl)-N'-(2-chloro-5-ethylphenyl)guanidinemesylate (Formula I: mesylate of R=3-ethylphenyl, R¹ =R² ═H, R³ =Cl, R⁴=CH₂ CH₃, n=0).

Part 1: Preparation of 2-chloro-5-ethylphenylcyanamide

To a heterogeneous slurry of 2-chloro-5-ethylaniline (1.6 g, 10 mmol) in60 mL of water at 4° C. was added solid BrCN (0.848 g, 8 mmol) slowly.After 5 minutes the cooling bath was removed and the heterogeneousreaction mixture was stirred at room temperature for 24 hours to yieldthe product in water suspension. The precipitates were collected byfiltration, washed with water (100 mL), and dried under vacuum to yieldthe pure title compound (1.45 g, 80% yield).

Part 2: Guanidine Synthesis

A mixture of 2-chloro-5-ethylphenylcyanamide (0.6 g, 3.08 mmol),3-ethylaniline mesylate (0.64 g, 2.93 mmol), and chlorobenzene (12 mL)were combined in a dry round bottom flask equipped with a water cooledcondenser under nitrogen and placed in a preheated oil bath (150-160°C.). The reaction mixture was heated for 3 hours. After cooling, thecrude reaction product was purified by crystallization fromchlorobenzene/diethylether. The resulting crystals were collected byfiltration, washed with diethylether, and dried in a vacuum oven (40°C., 15 hours) to yield the title compound,N-(3-ethylphenyl)-N'-(2-chloro-5-ethylphenyl)guanidine mesylate, as awhite solid (1.1 g, 91% yield).

TLC: R_(f) =0.4 (10% MeOH/CH₂ Cl₂); mp: 162-163° C.; ¹ H NMR (300 MHz,CD₃ OD): δ 7.48-7.17 (m, 7H, Ar--H), 2.69 (s, 3H, SO₃ CH₃), 2.67 (q,J=7.6 Hz, 4H), (H₂), 1.24 (t, J=7.5 Hz, 6H, CH₃); Anal.: C₁₈ H₂₄ ClN₃SO₃ ; Calcd. (%): C: 54.33, H: 6.08, N: 10.56; Found (%): C: 53.98, H:6.14, N: 10.40.

EXAMPLE 5

Other substituted aniline intermediates, suitable for reaction with anappropriate cyanamide compound to provide compounds of the invention asdescribed above, are either commercially available or can be prepared bymethods generally known to those skilled in the synthesis art. Thefollowing Examples 5a through 5d disclose procedures for preparation offour different substituted aniline compounds that are suitably used toprepare compounds of the invention, including e.g. the compounds ofExamples 23, 58, 64, 69 and 70 which follow.

EXAMPLE 5a

Preparation of 2-Bromo-5-methylthioaniline hydrochloride

To a stirred solution (cooled to 16-19° C.) of2-bromo-5-(methylthio)benzoic acid (1.5 g, 6.07 mmol, prepared by themethod described in Kuenzle, F., et al., Helv. Chim. Acta.,52(3):622-628 (1969)) in DMF (17 mL) was added triethylamine (1.05 mL,7.28 mmol). After stirring briefly, diphenyphosphoryl azide (1.7 mL,7.59 mmol) was added by an addition funnel over a 15 minute period.After 2 hours of stirring at ambient temperature, thin layerchromatography (SiO₂, cyclohexane/ethyl acetate 8:1) showed the reactionwas completed. To this solution was added distilled water (7 mL) and themixture was then heated to 65° C. for 2 hours.

The reaction mixture was concentrated in vacuo at 45° C. to afford alight yellow, syrupy residue. After adding water (50 mL) to thisresidue, saturated potassium carbonate was added until pH 9. The mixturewas then extracted with 40 mL of methylene chloride two times. Thecombined extracts were washed with brine, dried over MgSO₄ andconcentrated in vacuo to yield a yellow oil. The yellow oil wasdissolved in 10 mL of ether and added HCl/ether (10 mL, 1N) to provide awhite precipitate. The solid was collected by filtration and furtherpurified by column chromatography (SiO2₂, hexanes/EtOAc: 100% -80%). Thefinal product was a white solid (0.6 g, 39% in yield); ¹ H NMR (CD₃ OD):δ (ppm) 7.76 (d, 1H, 8.5 Hz), 7.20 (s, 1H), 7.18 (d, 1H), 2.50 (s, 3H,CH₃); Anal: C₇ H₈ BrNS.HCl; Calcd. (%): C: 33.03, H: 3.56, N: 5.50;Found (%): C: 33.00, N: 3.52, N: 5.59.

EXAMPLE 5b

Preparation of N-Methyl-3-methylsulfinylaniline hydrochloride

Part 1: N-Methyl-(3-methylthiophenyl)amine:

3-Methylmercaptoaniline (5 g, 34.8 mmol) was dissolved in formic acid(1.92 mL, 49 mmol) and heated to 100-105° C. under argon for overnight.The reaction mixture was cooled to room temperature and extracted withCH₂ Cl₂ (75 ml). The organic layer was washed with saturated Na₂ CO₃ (30ml) three times and dried over MgSO₄, filtered to remove MgSO₄ and thesolution concentrated to afford the formamide. The formamide wasdissolved in anhydrous THF (30 ml) under argon. To this solution wasadded slowly LiAlH₄ in THF (50 ml, 1 M) at 0-5° C. The reaction waswarmed up to room temperature and stirred for 20 hours. To this reactionmixture was added 50 ml of saturated aqueous MgSO₄. The organic layerwas saved. The water layer was further extracted with ethyl acetate (50ml) three times and the combined organic solution was washed with H₂ O(50 ml), brine (50 ml) and dried over MgSO₄. The solution was filteredto remove MgSO₄ and then concentrated to yield the crude product whichwas purified by column chromatography (SiO₂, hexanes/EtOAc: 8/1). Thefractions which contained the product were collected and concentrated,dried under vacuum to yield the pure N-Methyl-(3-methylthiophenyl)amine(5.25 g, 98% in yield).

Part 2: N-Methyl-3-methylsulfinylaniline hydrochloride

Hydrogen peroxide (30% in water, 10.22 mL, 1 mol, Aldrich) was added toa solution of N-methyl-3-methylmercaptoaniline (3.0 g, 19.6 mmol) inacetone (17 mL) at 0-5° C. The reaction was stirred overnight and thenthe acetone was removed. A 1N NaOH aqueous solution was added until pH12, which was then extracted with ether (30 ml) three times. Thecombined organic layers were dried over MgSO₄, and then the solution wasfiltered to remove MgSO₄ and the resulting solution concentrated toyield the crude product of the title compound which was purified bycolumn chromatography (silica gel, eluted by EtOAc/MeOH: 100% -90%).N-Methyl-3-methylsulfinylaniline was obtained and was further convertedto its hydrochloride salt (1.82 g, 45% in yield).

¹ H NMR (CD₃ OD): δ (ppm) 7.90-7.55 (m, Ar--H, 4H), 3.11 (s, NCH₃, 3H),2.85 (s, SOCH₃, 3H); MS(EI): m/e 169 (M⁺ for the free base); TLC: R_(f)=0.29 (SiO₂, EtOAc); M.P.: 137-138° C.

EXAMPLE 5c

Preparation of N-Methyl-3-methylsulfonyl aniline hydrochloride

Hydrogen peroxide (30% in water, 10.22 mL, 1 mol, Aldrich) was added toa solution of N-methyl-3-methylmercaptoaniline (3.0 g, 19.6 mmol) inacetone (17 mL) at 0-5° C. The reaction was stirred for overnight andthen the acetone was removed. A 1N NaOH aqueous solution was added untilpH 12, which solution was then extracted with 30 ml of ethyl ether threetimes and the combined organic layers were dried MgSO₄. The MgSO₄ wasremoved by filtration and the resulting solution was concentrated toyield the crude product which was purified by column chromatography(silica gel, eluted by EtOAc/MeOH 100% -90%). N-methyl-3-methylsulfonylaniline was obtained and further converted to its hydrochloride salt(1.8 g, 42% in yield).

¹ H NMR (CD₃ OD): δ (ppm) 7.90-7.50 (m, Ar--H, 4H), 3.16 (s, SO₂ CH₃,3H), 3.05 (s, NCH₃, 3H); MS(EI): m/e 185 (M⁺ : C₈ H₁₁ NSO₂); TLC: R_(f)=0.81 (SiO₂, EtOAc); M.P.: 169-170° C.

EXAMPLE 5d

Preparation of 2-Fluoro-5-ethylaniline

Part 1: 3'-Nitro-4'-fluoroacetophenone:

To stirred, pre-cooled fuming nitric acid (40 mL) at -10° C. was addeddropwise 4'-fluoroacetophenone (Aldrich, 75 g, 54.3 mmol) over a periodof 10 minutes. The temperature was strictly maintained at -9 to -10° C.for a total of 8 hours. The reaction mixture flask was then transferredto the freezer (-10° C.) for storage overnight. In the morning thereaction mixture was poured onto ice (1.5 Kg). The resultant mixture wasextracted three times with ether (400 mL). The organic layer was washedfour times with NaOH (1N, 300 mL) and brine. Concentration in vacuoafforded a yellow liquid which by thin layer chromatography (SiO₂,cyclohexane/ethyl acetate: 2/1) showed one major and two minor products.The crude product was purified over 600 grams of 230-400 mesh silicagel, eluting with a gradient of hexanes-ethyl acetate 10:1 to 3:1. Theproduct containing fractions were concentrated to afford a light yellowliquid (27.6 grams).

Part 2: 3'-Amino-4'-fluoroacetophenone:

To a stirred mixture of 3'-nitro-4'-fluoroacetophenone (10.04 g, 55mmol) in 72 mL of concentrated hydrochloric acid, was added tin (II)chloride dihydrate (37 grams), in portions. After approximately onethird of the material had been added, a rapid rise in the internalreaction temperature (to 95° C.) was noted. The mixture was then heatedto reflux for 10 minutes, this resulted in the dissolution of all solidsto give a solution. The mixture was then cooled to room temperature andpoured onto an ice/water mixture (150 g). The mixture was then furthercooled in an ice bath while 50% sodium hydroxide was added until pH 12was reached. The aqueous layer was extracted twice with ether (50 mL).The combined organic extracts were washed with brine and then dried oversodium sulfate. Removal of the drying agent and in vacuo concentrationof the filtrate afforded a yellow-orange oil (8.73 g) which wasrecrystallized on standing. This material was of sufficient purity to beused directly in the next step (Part 3).

Part 3: 2-Fluoro-5-ethylaniline:

To a stirred mixture of 3'-amino-4'-fluoroacetophenone (7.56 g, 49.4mmol) in triethylene glycol (60 mL) was added 4.94 g of sodiumhydroxide. Neat hydrazine hydrate (7.2 mL) was added to the mixture inone portion via a syringe. This addition resulted in a slight exotherm(temperature around 50°). The reaction flask (three neck, equipped withclaisen adapter and receiving flask) was then equipped with a heatingmantle and the reaction heated to 100° C. for 1 hour, then 150° C. Atthe higher temperature distillate began to collect in the receivingflask. After 1 hour at 150° C. the reaction mixture was then heated to180° C., while still collecting distillate. After 45 minutes at 180° C.thin layer chromatography indicated the complete absence of startingmaterial and the appearance of a single major product. The reactionmixture was cooled to room temperature with an ice bath and poured into100 mL of water. The aqueous mixture was extracted three times withether (125 mL). The combined organic extracts were washed once withwater, once with brine and then dried over potassium carbonate.Concentration of the organic extracts in vacuo afforded2-fluoro-5-ethylaniline (6.82 g) as an amber liquid. This material wasfurther purified by column chromatography (silica gel, hexanes/ethylacetate: 2/1) to give 7.11 grams of product as a viscous liquid.

¹ H NMR (CDCl₃): δ (ppm) 8.0-7.0 (m, Ar--H), 2.52 (q, CH₂), 1.20 (t,CH₃); MW: 139.18 (for the free base); Anal.: C₈ H₁₀ NF; Calcd. (%): C:69.04, H: 7.24, N: 10.07; Found (%): C: 69.03; N: 7.49, N: 9.89.

EXAMPLES 6-73

By procedures similar to those employed in Examples 1 through 5 abovebut using appropriately substituted amine hydrochloride and cyanamidereagents, the following compounds of Formulas I and II were preparedhaving the specified physical characteristics.

EXAMPLE 6

N-(3-Ethylphenyl)-N-methyl-N'-(2,5-dichlorophenyl)-N'-methylguanidinehydrochloride (Formula I: hydrochloride salt of R=3-ethylphenyl, R¹ =R²═CH₃, R₃ =R₄ ═Cl, n=0).

white solid; TLC: R_(f) =0.4 (10% MeOH/CH₂ Cl₂); mp: 161-162° C.; ¹ HNMR (300 MHz, CD₃ OD): δ 7.38-7.09 (m, 7H, Ar--H), 3.44 (s, 3H, CH₃),3.38 (s, 3H, CH₃), 2.51 (q, J=7.6 Hz, 2H, CH₂), 1.16 (t, J=7.6 Hz, 3H,CH₃); Anal.: (C₁₇ H₁₉ Cl₂ N₃.HCl.H₂ O); Calcd. (%): C: 52.26, H: 5.68,N: 10.75; Found (%): C: 51.94, H: 5.59, N: 10.44.

EXAMPLE 7

N-(3-Ethylphenyl)-N'-(2,5-dichlorophenyl)-N'-methylguanidinehydrochloride (Formula I: hydrochloride salt of R=3-ethylphenyl, R¹ =H,R² =CH₃, R³ =R⁴ ═Cl, n=0).

white solid; TLC: R_(f) =0.4 (10% MeOH/CH₂ Cl₂); mp=92-93° C., ¹ H NMR(300 MHz, CD₃ OD): δ 7.76-7.12 (m, 7H, Ar--H), 3.44 (s, 3H, CH₃), 2.68(q, J=7.6 Hz, 2H, CH₂), 1.24 (t, J=7.6 Hz, 3H, CH₃); Anal.: (C₁₆ H₁₇ Cl₂N₃.HCl), Calcd. (%) C: 53.58, H: 5.06, N: 11.91; Found (%): C: 53.49, H:5.20, N: 11.92; MS (EI)=m/e 321 (M⁺ for the free base).

EXAMPLE 8

N-(3-Ethylphenyl)-N'-(2,5-dichlorophenyl)guanidine hydrochloride(Formula I: hydrochloride salt of R=3-ethylphenyl, R¹ =R² ═H, R³ =R⁴═Cl, n=0).

white solid; TLC: R_(f) =0.4 (10% MeOH/CH₂ Cl₂); mp: 111-112° C.; ¹ HNMR (300 MHz, CD₃ OD): δ 7.58-7.15 (m, 7H, Ar--H), 2.68 (q, J=7.6 Hz,2H, CH₂), 1.24 (t, J=7.6 Hz, 3H, CH₃); MS (EI): m/e 308 (M⁺ for the freebase); Anal.: (C₁₅ H₁₅ Cl₂ N₃.HCl); Calcd. (%): C: 52.27, H: 4.68, N:12.19; Found (%): C: 52.17, H: 4.76, N: 12.25.

EXAMPLE 9

N-(3-Ethylphenyl)-N-methyl-N'-(2,5-dibromophenyl)-N'-methylguanidinehydrochloride (Formula I: hydrochloride salt of R=3-ethylphenyl, R¹ =R²═CH₃, R³ =R⁴ ═Br, n=0).

white solid; TLC: R_(f) =0.3 (10% MeOH/CH₂ Cl₂); mp: 179-180° C.; ¹ HNMR (300 MHz, CD₃ OD): δ 7.48-7.10 (m, 7H, Ar--H), 3.45 (s, 3H, CH₃),3.38 (s, 3H, CH₃), 2.52 (q, J=7.7 Hz, 2H, CH₂), 1.18 (t, J=7.7 Hz, 3H,CH₃); MS (EI): m/e 425 (M⁺ for the free base); Anal.: (C₁₇ H₁₉ Br₂N₃.HCl); Calcd. (%): C: 44.23, H: 4.37, N: 9.10; Found (%): C: 44.00, H:4.57, N: 9.04.

EXAMPLE 10

N-(3-Ethylphenyl)-N'-(2,5-dibromophenyl)guanidine hydrochloride (FormulaI: hydrochloride salt of R=3-ethylphenyl, R¹ =R² ═H, R³ =R⁴ ═Br, n=0).

white solid; TLC: R_(f) =0.54 (10% MeOH/CH₂ Cl₂); mp: 76-77° C.; ¹ H NMR(300 MHz, CD₃ OD): δ 7.70-7.15 (m, 7H, Ar--H), 2.67 (q, J=7.6 Hz, 2H,CH₂), 1.24 (t, J=7.6 Hz, 3H, CH₃); MS (EI): m/e 397 (M⁺ for the freebase); HRMS: 394.9618 (394.9632 calculated for C₁₅ H₁₅ Br₂ N₃).

EXAMPLE 11

N-(3-Ethylphenyl)-N-methyl-N'-(2-chloro-5-trifluoromethylphenyl)guanidinehydrochloride (Formula I: hydrochloride salt of R=3-ethylphenyl, R¹=CH₃, R² =H, R³ =Cl, R⁴ =CF₃, n=0).

white solid; TLC: R_(f) =0.5 (10% MeOH/CH₂ Cl₂); mp: 180-181° C.; ¹ HNMR: δ 7.76-7.25 (m, 7H, Ar--H), 3.53 (s, 3H, CH₃), 2.70 (q, J=7.5 Hz,2H, CH₂), 1.26 (t, J=7.5 Hz, 3H, CH₃); MS (EI): m/e 355 (M⁺ for the freebase); Anal.: (C₁₇ H₁₇ ClF₃ N₃.HCl); Calcd. (%): C: 52.05, H: 4.63, N:10.71; Found (%): C: 52.15, H: 4.53, N: 10.72.

EXAMPLE 12

N-(3-Ethylphenyl)-N'-(2-chloro-5-trifluoromethylphenyl)guanidinehydrochloride (Formula I: hydrochloride salt of R=3-ethylphenyl, R¹ =R²═H, R³ =Cl, R⁴ =CF₃, n=0).

white solid; TLC: R_(f) =0.4 (10% MeOH/CH₂ Cl₂); mp: 73-74° C.; ¹ H NMR:δ 7.55-7.16 (m, 7H, Ar--H), 2.60 (q, J=7.6 Hz, 2H, CH₂), 1.21 (t, J=7.6Hz, 3H, CH₃); MS (EI): m/e 341 (M⁺ for the free base); HRMS: 341.0907(341.0917 calculated for C₁₆ H₁₅ ClF₃ N₃).

EXAMPLE 13

N-(3-Ethylphenyl)-N-methyl-N'-(2-bromo-5-trifluoromethylphenyl)guanidinehydrochloride (Formula I: hydrochloride salt of R=3-ethylphenyl, R¹=CH₃, R² =H, R³ =Br, R⁴ =CF₃, n=0).

white solid; TLC: R_(f) =0.5 (10% MeOH/CH₂ Cl₂); mp: 184-185° C.; ¹ HNMR: δ 7.93-7.28 (m, 7H, Ar--H), 3.50 (s, 3H, CH₃), 2.70 (q, J=7.6 Hz,2H, CH₂), 1.25 (t, J=7.6 Hz, 3H, CH₃); MS (EI): m/e 400 (M⁺ for the freebase); Anal.: (C₁₇ H₁₇ BrF₃ N₃.HCl); Calcd. (%): C: 46.76, H: 4.15, N:9.62; Found (%): C: 46.57, H: 4.12, N: 9.36.

EXAMPLE 14

N-(3-Ethylphenyl)-N'-(2-bromo-5-trifluoromethylphenyl)guanidinehydrochloride (Formula I: hydrochloride salt of R=3-ethylphenyl, R¹ =R²═H, R³ =Br, R⁴ =CF₃, n=0).

white solid; TLC: R_(f) =0.4 (10% MeOH/CH₂ Cl₂); mp: 109-1 10° C.; ¹ HNMR: δ 7.77-7.17 (m, 7H, Ar--H), 2.61 (q, J=7.7 Hz, 2H, CH₂); MS(EI):m/e 386 (M⁺ for the free base); HRMS: 385.0391 (385.0401 calculated forC₁₆ H₁₅ BrF₃ N₃).

EXAMPLE 15

N-(3-Ethylphenyl)-N-methyl-N'-(2-fluoro-5-trifluoromethylphenyl)guanidinehydrochloride (Formula I: hydrochloride salt of R=3-ethylphenyl, R¹=CH₃, R² =H, R³ =F, R⁴ =CF₃, n=0).

white solid; TLC: R_(f) =0.5 (10% MeOH/CH₂ Cl₂); mp: 158-159° C.; ¹ HNMR: δ 8.20-7.20 (m, 7H, Ar--H), 3.43 (s, 3H, CH₃), 2.61 (q, J=7.6 Hz,2H, CH₂), 1.17 (t, J=7.6 Hz, 3H, CH₃); MS (EI): m/e 339 (M⁺ for the freebase); Anal.: (C₁₇ H₁₇ F₄ N₃.HCl); Calcd. (%): C: 54.33, H: 4.83, N:11.18; Found (%): C: 54.20, H: 4.90, N: 11.04.

EXAMPLE 16

N-(3-Ethylphenyl)-N'-(2-fluoro-5-trifluoromethylphenyl)guanidinehydrochloride (Formula I: hydrochloride salt of R=3-ethylphenyl, R¹ =R²═H, R³ =F, R⁴ =CF₃, n=0).

white solid; TLC: R_(f) =0.4 (10% MeOH/CH₂ Cl₂); mp: 105-106° C.; ¹ HNMR: δ 7.25-6.85 (m, 7H, Ar--H), 2.60 (q, J=7.7 Hz, 2H, CH₂), 1.21 (t,J=7.6 Hz, 3H, CH₃); MS (EI): m/e 325 (M⁺ for the free base); HRMS:325.1212 (325.1202 calculated for C₁₆ H₁₅ N₃ F₄).

EXAMPLE 17

N-(3-Ethylphenyl)-N-methyl-N'-(2-chloro-5-ethylphenyl)-N'-methylguanidinehydrochloride (Formula I: hydrochloride salt of R=3-ethylphenyl, R¹ =R²═CH₃, R³ =Cl, R⁴ =CH₂ CH₃, n=0).

white solid; TLC: R_(f) =0.3 (10% MeOH/CH₂ Cl₂); mp: 129-130° C.; ¹ HNMR (300 MHz, CD₃ OD): δ 7.28-7.01 (m, 7H, Ar--H), 3.42 (s, 3H, CH₃),3.39 (s, 3H, CH₃), 2.49 (q, J=7.6 Hz, 2H, CH₂), 2.34 (q, J=7.6 Hz, 2H,CH₂), 1.13 (t, J=7.7 Hz, 3H, CH₃), 1.05 (t, J=7.7 Hz, 3H, CH₃); MS (EI):m/e 330 (M⁺ for the free base).

EXAMPLE 18

N-(3-Ethylphenyl)-N-methyl-N'-(2-chloro-5-ethylphenyl)guanidinehydrochloride (Formula I: hydrochloride salt of R=3-ethylphenyl, R¹=CH₃, R² =H, R³ =Cl, R⁴ =CH₂ CH₃, n=0).

white solid; TLC: R_(f) =0.4 (10% MeOH/CH₂ Cl₂); mp: 190-191° C.; ¹ HNMR (300 MHz, CD₃ OD): δ 7.44-7.20 (m, 7H, Ar--H), 3.48 (s, 3H, CH₃),2.71 (q, J=7.6 Hz, 2H, CH₂), 2.65 (J=7.6 Hz, 2H, CH₂), 1.27 (t, J=7.7Hz, 3H, CH₃), 1.23 (t, J=7.7 Hz, 3H, CH₃); MS (EI): m/e 315 (M⁺ for thefree base); Anal.: (C₁₈ H₂₂ ClN₃.HCl); Calcd. (%): C: 61.36, H: 6.58, N:11.93; Found (%): C: 61.09, H: 6.37, N: 11.86.

EXAMPLE 19

N-(3-Ethylphenyl)-N'-(2-chloro-5-ethylphenyl)guanidine hydrochloride(Formula I: hydrochloride salt of R=3-ethylphenyl, R¹ =R² ═H, R³ =Cl, R⁴=CH₂ CH₃, n=0).

white solid; TLC: R_(f) =0.5 (10% MeOH/CH₂ Cl₂); mp: 77-78° C.; ¹ H NMR(300 MHz, CD₃ OD): δ 7.49-7.18 (m, 7H, Ar--H), 2.69 (q, J=7.6 Hz, 4H,CH₂), 1.24 (t, J=7.6 Hz, 6H, CH₃); MS (EI): m/e301 (M⁺ for the freebase); Anal.: (C₁₇ H₂₀ ClN₃.HCl); Calcd. (%): C: 60.36, H: 6.26, N:12.42; Found (%): C: 60.33, H: 6.42, N: 12.37.

EXAMPLE 20

N-(3-Ethylphenyl)-N-methyl-N'-(2-bromo-5-ethylphenyl)guanidinehydrochloride (Formula I: hydrochloride salt of R=3-ethylphenyl, R¹=CH₃, R² =H, R³ =Br, R⁴ =CH₂ CH₃, n=0).

white solid; TLC: R_(f) =0.4 (10% MeOH/CH₂ Cl₂); mp: 189-190° C.; ¹ HNMR (300 MHz, CD₃ OD): δ 7.62-7.18 (m, 7H, Ar--H), 3.49 (s, 3H, CH₃),2.71 (q, J=7.6 Hz, 2H, CH₂), 2.64 (q, J=7.6 Hz, 2H, CH₂), 1.26 (t, J=7.6Hz, 3H, CH₃), 1.23 (t, J=7.7 Hz, 3H, CH₃); MS (EI): m/e 360 (M⁺ for thefree base); Anal.: (C₁₈ H₂₂ BrN₃.HCl); Calcd. (%): C: 54.49, H: 5.84, N:10.59; Found (%): C: 54.46, H: 5.95, N: 10.62.

EXAMPLE 21

N-(3-Ethylphenyl)-N'-(2-bromo-5-ethylphenyl)guanidine hydrochloride(Formula I: hydrochloride salt of R=3-ethylphenyl, R¹ =R² ═H, R³ =Br, R⁴=CH₂ CH₃, n=0).

white solid; TLC: R_(f) =0.54 (10% MeOH/CH₂ Cl₂); mp: 70-71° C.; ¹ H NMR(300 MHz, CD₃ OD): δ 7.62-7.10 (m, 7H, Ar--H), 2.71-2.62 (m, 4H, CH₂),1.27 (t, J=7.6 Hz, 3H, CH₃), 1.22 (t, J=7.7 Hz, 3H, CH₃); Anal.: (C₁₇H₂₀ BrN₃.HCl); Calcd. (%): C: 53.35, H: 5.53, N: 10.98; Found (%): C:53.61, H: 5.56, N: 11.04; MS(EI): m/e 345 (M⁺ for the free base).

EXAMPLE 22

N-(3-Ethylphenyl)-N-methyl-N'-(2-fluoro-5-ethylphenyl)guanidinehydrochloride (Formula I: hydrochloride salt of R=3-ethylphenyl, R¹=CH₃, R² =H, R³ =F, R⁴ =CH₂ CH₃, n=0).

white solid; TLC: R_(f) =0.4 (10% MeOH/CH₂ Cl₂); mp: 171-172° C.; ¹ HNMR (300 MHz, CD₃ OD): δ 7.45-7.14 (m, 7H, Ar--H), 3.48 (s, 3H, CH₃),2.70 (q, J=7.6 Hz, 2H, CH₂), 2.64 (q, J=7.5 Hz, 2H, CH₂), 1.26 (t, J=7.7Hz, 3H, CH₃), 1.22 (t, J=7.5 Hz, 3H, CH₃); MS (EI): m/e 299 (M⁺ for thefree base); Anal.: (C₁₈ H₂₂ FN₃.HCl); Calcd. (%): C: 64.37, H: 6.90, N:12.51; Found (%): C: 64.49, N: 7.01, N: 12.45.

EXAMPLE 23

N-(3-Ethylphenyl)-N'-(2-fluoro-5-ethylphenyl)guanidine hydrochloride(Formula I: hydrochloride salt of R=3-ethylphenyl, R¹ =R² ═H, R³ =F, R⁴=CH₂ CH₃, n=0).

white solid; TLC: R_(f) =0.3 (10% MeOH/CH₂ Cl₂); mp=52.53° C.; ¹ H NMR(300 MHz, CD₃ OD): δ 7.34-7.11 (m, 7H, Ar--H), 2.70-2.61 (m, 4H, CH₂),1.26-1.20 (m, 6H, CH₃); Anal.: (C₁₇ H₂₀ FN₃.HCl); Calcd. (%): C: 63.45,H: 6.58, N: 13.06; Found (%): C: 63.52, H: 6.77, N: 13.32; MS(EI): m/e285 (M⁺ for the free base).

EXAMPLE 24

N-(3-Ethylphenyl)-N-methyl-N'-(2-chloro-5-methylphenyl)guanidinehydrochloride (Formula I: hydrochloride salt of R=3-ethylphenyl, R¹=CH₃, R² =H, R³ =Cl, R⁴ =CH₃, n=0).

white solid; TLC: R_(f) =0.45 (10% MeOH/CH₂ Cl₂); mp: 204-205° C.; ¹ HNMR (300 MHz, CD₃ OD): δ 7.46-7.16 (m, 7H, Ar--H), 3.48 (s, 3H, CH₃),2.70 (q, J=7.6 Hz, 2H, CH₂), 2.33 (s, 3H, CH₃), 1.26 (t, J=7.6 Hz, 3H,CH₃); MS (EI): m/e 302 (M⁺ for the free base); Anal.: (C₁₇ H₂₀ClN₃.HCl); Calcd. (%): C: 60.36, H: 6.26, N: 12.42; Found (%): C: 60.23,H: 6.50, N: 12.32.

EXAMPLE 25

N-(3-Ethylphenyl)-N'-(2-chloro-5-methylphenyl)guanidine hydrochloride(Formula I: hydrochloride salt of R=3-ethylphenyl, R¹ =R² ═H, R³ =Cl, R⁴=CH₃, n=0).

white solid; TLC: R_(f) =0.35 (10% MeOH/CH₂ Cl₂); mp: 88-89° C.; ¹ H NMR(300 MHz, CD₃ OD): δ 7.45-7.18 (m, 7H, Ar--H), 2.69 (q, J=7.7 Hz, 2H,CH₂), 2.37 (s, 3H, CH₃), 1.25 (t, J=7.7 Hz, 3H, CH₃); MS (EI): m/e 288(M⁺ for the free base); Anal.: (C₁₆ H₁₈ ClN₃.HCl.0.5H₂ O); Calcd. (%):C: 57.66, H: 6.05, N: 12.61; Found (%): C: 57.36, H: 6.08, N: 12.46.

EXAMPLE 26

N-(3-Ethylphenyl)-N-methyl-N'-(2-chloro-5-methylthiophenyl)guanidinehydrochloride (Formula I: hydrochloride salt of R=3-ethylphenyl, R¹=CH₃, R² =H, R³ =Cl, R⁴ =SCH₃, n=0).

white solid; TLC: R_(f) =0.45 (10% MeOH/CH₂ Cl₂); mp: 198-199° C.; MS(EI): m/e 333 (M⁺ for the free base); ¹ H NMR (CD₃ OD): δ 7.45-7.20 (m,7H, Ar--H), 3.49 (s, 3H, CH₃), 2.70 (q, J=7.5 Hz, 2H, CH₂), 2.49 (s, 3H,SCH₃), 1.26 (t, J=7.5 Hz, 3H, CH₃); Anal.: (C₁₇ H₂₀ ClN₃ S.HCl); Calcd.(%): C: 55.14, H: 5.72, N: 11.35; Found (%): C: 54.99, H: 5.63, N:11.23.

EXAMPLE 27

N-(3-Ethylphenyl)-N'-(2-chloro-5-methylthiophenyl)guanidinehydrochloride (Formula I: hydrochloride salt of R=3-ethylphenyl, R¹ =R²═H, R³ =Cl, R⁴ =SCH₃, n=0).

white solid; TLC: R_(f) =0.45 (10% MeOH/CH₂ Cl₂); mp=132-133° C.; ¹ HNMR (CD₃ OD): δ 7.50-7.18 (m, 7H, Ar--H), 2.69 (q, J=7.6 Hz, 2H, CH₂),2.51 (s, 3H, CH₃), 1.25 (t, J=7.6 Hz, 3H, CH₃); Anal.: (C₁₆ H₁₈ ClN₃S.HCl); Calcd. (%): C: 53.93, N: 11.79, H: 5.37; Found (%): C: 54.09, N:11.72, H: 5.44.

EXAMPLE 28

N-(1-Naphthyl)-N'-(2-fluoro-5-methylphenyl)guanidine hydrochloride(Formula I: hydrochloride salt of R=1-naphthyl, R¹ =R² ═H, R³ =F, R⁴=CH₃, n=0).

white solid; mp 194° C.; ¹ H NMR (300 MHz, CD₃ OD): δ 7.98-8.15 (m, 2,Ar--H), 7.57-7.68 (m, 3, Ar--H) 7.15-7.24 (d, 5, Ar--H); 2.35 (s, 3,CH₃); MS (EI); m/e 293 (M⁺ for free base).

EXAMPLE 29

N-(1-Naphthyl)-N'(2,5-dichlorophenyl)-N'-methylguanidine hydrochloride(Formula I: hydrochloride salt of R=1-naphthyl, R¹ =H, R² =CH₃, R³ =R⁴═Cl, n=0).

white solid; mp 210° C., ¹ H NMR (300 MHz, CD₃ OD): δ 7.96-8.02 (m, 3,Ar--H), 7.48-7.64 (m, 7, Ar--H); 3.52 (s, 3, N--CH₃); MS (EI): m/e 344(M⁺ for free base); Anal.: (C₁₈ H₁₅ Cl₂ N₃.HCl.0.25 H₂ O); Calcd. (%):C: 56.13, H: 4.32, N: 10.91; Found (%): C: 56.02, H: 4.60, N: 10.73.

EXAMPLE 30

N-(1-Naphthyl)-N'(2-chloro-5-methylphenyl)guanidine hydrochloride(Formula I: hydrochloride salt of R=1-naphthyl, R¹ =R² ═H, R³ =Cl, R⁴=CH₃, n=0).

white solid; mp 125° C.; ¹ H NMR (300 MHz, CD₃ OD): δ 7.95-8.10 (m, 3,Ar--H), 7.52-7.70 (m, 6, Ar--H); 7.41-7.48 (d, 1, Ar--H); 7.30-7.35 (s,1, Ar--H); 7.20-7.25 (m, 2, Ar--H); 2.37 (s, 3, Ar--CH₃); MS (EI): m/e310 (M⁺ for free base); Anal.: (C₁₈ H₁₆ ClN₃.HCl); Calcd. (%): C: 62.44,H: 4.95, N: 12.14; Found (%): C: 62.52, H: 5.04, N: 11.96.

EXAMPLE 31

N-(1-Naphthyl)-N'-(2,5-dimethylphenyl)guanidine hydrochloride (FormulaI: hydrochloride salt of R=1-naphthyl, R¹ =R² ═H, R³ =R⁴ ═CH₃, n=0).

white solid; mp 122-123° C.; ¹ H NMR (300 MHz, CD₃ OD): δ 7.95-8.08 (m,3, Ar--H), 7.55-7.71 (m, 4, Ar--H); 7.10-7.28 (m, 3, Ar--H); 2.32 (s, 6,2 Ar--CH₃); MS (EI): m/e 289 (M⁺ for free base); Anal.: (C₁₉ H₁₉N₃.HCl); Calcd. (%): C: 70.04, H: 6.19, N: 12.90; Found (%): C: 70.02,H: 6,20, N: 12.87.

EXAMPLE 32

N-(1-Naphthyl)-N'-(2,5-dibromophenyl)guanidine hydrochloride (Formula I:hydrochloride salt of R=1-naphthyl, R¹ =R² ═H, R³ =R⁴ ═Br, n=0).

white solid; mp 231-232° C.; ¹ H NMR (300 MHz, CD₃ OD): δ 7.97-8.13 (m,3, Ar--H), 7.48-7.72 (m, 7, Ar--H); MS (EI): M/e 419 (M⁺ for free base).

EXAMPLE 33

N-(1-Naphthyl)-N'-(2-chloro-5-methylphenyl)-N'-methylguanidinehydrochloride (Formula I: hydrochloride salt of R=1-naphthyl, R¹ =H, R²=CH₃, R³ =Cl, R⁴ =CH₃, n=0).

white solid; mp 228-229° C.; ¹ H NMR (300 MHz, CD₃ OD): δ 7.96-7.99 (m,3, Ar--H), 7.48-7.61 (m, 6, Ar--H); 7.26-7.30 (d, 1, Ar--H); 3.50 (s, 3,N--CH₃); 2.39 (s, 3, Ar--CH₃)I MS (EI): m/e 324 (M⁺ for free base);Anal.: (C₁₉ H₁₈ ClN₃.HCl); Calcd. (%): C: 63.34, H: 5.32, N: 11.66;Found (%): C: 63.20, H: 5.43, N: 11.66.

EXAMPLE 34

N-(1-Naphthyl)-N'-(2,5-dimethylphenyl)-N'-methylguanidine hydrochloride(Formula I: hydrochloride salt of R=1-naphthyl, R¹ =H, R² =CH₃, R³ =R⁴═CH₃, n=0).

white solid; mp 216-217° C.; ¹ H NMR (300 MHz, CD₃ OD): δ 7.95-8.00 (m,2, Ar--H), 7.5-7.7 (m, 4, Ar--H); 7.18-7.38 (m, 4, Ar--H); 3.5 (br s, 3,N--CH₃); 2.38 (s, 3, Ar--CH₃); MS (EI): m/e 303 (M⁺ for free base);Anal.: (C₂₀ H₂₁ N₃.HCl); Calcd. (%): C: 70.68, H: 6,52, N: 12.36; Found(%): C: 70.51, H: 6,46, N: 12.18.

EXAMPLE 35

N-(1-Naphthyl)-N'-(2,5-dibromophenyl)-N-methylguanidine hydrochloride(Formula I: hydrochloride salt of R=1-naphthyl, R¹ =H, R² =CH₃, R³ =R⁴═Br, n=0).

white solid; mp 213° C.; ¹ H NMR (300 MHz, CD₃ OD): δ 7.94-8.06 (m, 3,Ar--H), 7.54-7.74 (m, 6, Ar--H); 7.2-7.38 (m, 1, Ar--H); 3.5 (br, s,N--CH₃); MS (EI): m/e 433 (M⁺ for free base); Anal.: (C₁₈ H₁₅ Br₂N₃.HCl); Calcd. (%): C: 46.04, H: 3.43, N: 8.95; Found (%): C: 46.15, H:3.33, N: 8.89.

EXAMPLE 36

N-(1-Naphthyl)-N'-(2-chloro-5-thiomethylphenyl)guanidine hydrochloride(Formula I: hydrochloride salt of R=1-naphthyl, R¹ =R² ═H, R³ =Cl, R⁴=SCH₃, n=0).

white solid; mp 175° C.; ¹ H NMR (300 MHz, CD₃ OD): δ 7.95-8.10 (m, 3,AR--H), 7.55-7.70 (m, 4, Ar--H); 7.46-7.51 (d, J=8 Hz; 1, Ar--H);7.34-7.39 (s, 1, Ar--H); 7.25-7.32 (dd, 1, Ar--H); 2.51 (s, 3, S--CH₃);MS (EI): m/e 342 (M⁺ for free base); Anal.: (C₁₈ H₁₆ ClN₃ S.HCl.EtOH);Calcd. (%): C: 56.61, H: 5.23, N: 9.90; Found (%): C: 56.71, H: 5.21, N:10.19.

EXAMPLE 37

N-(1-Naphthyl)-N'-(2-fluoro-5-trifluoromethylphenyl)guanidinehydrochloride (Formula I: hydrochloride salt of R=1-naphthyl, R¹ =R² ═H,R³ =F, R⁴ =CF₃, n=0).

white solid; mp 149° C.; ¹ H NMR (300 MHz, CD₃ OD): δ 7.97-8.07 (m, 3,Ar--H), 7.48-7.85 (m, 7, Ar--H); MS (EI): m/e 347 (M⁺ for free base);Anal.: (C18H₁₃ F₄ N₃.HCl); Calcd. (%): C: 56.33, H: 3.68, N: 10.95;Found (%): C: 55.91, H: 3.69, N: 10.79.

EXAMPLE 38

N-(1-Naphthyl)-N'-(2-chloro-5-trifluoromethylphenyl)guanidinehydrochloride (Formula I: hydrochloride salt of R=1-naphthyl, R¹ =R² ═H,R³ =Cl, R⁴ =CF₃, n=0).

white solid; mp 198° C.; ¹ H NMR (300 MHz, CD₃ OD): δ 8.07-8.09 (d,J=8.5 Hz, 1, Ar--H), 7.98-8.01 (m, 2, Ar--H); 7.56-7.86 (m; 7, Ar--H);MS (EI): m/e 364 (M⁺ for free base); Anal.: (C₁₈ H₁₃ ClF₃ N₃.HCl);Calcd. (%): C: 54.02, H: 3.53, N: 10.50; Found (%): C: 54.16, H: 3.52,N: 10.35.

EXAMPLE 39

N-(1-Naphthyl)-N'-(2-bromo-5-trifluoromethylphenyl)guanidinehydrochloride (Formula I: hydrochloride salt of R=1-naphthyl, R¹ =R² ═H,R³ =Br, R⁴ =CF₃, n=0).

white solid; mp 234° C.; ¹ H NMR (300 MHz, CD₃ OD): δ 8.10-8.12 (d, J=9Hz, 1, Ar--H), 7.97-8.01 (m, 3, Ar--H); 7.86 (s, 1, Ar--H); 7.56-7.70(m, 5, Ar--H); MS (EI): m/e 408 (M⁺ for free base); Anal.: (C₁₈ H₁₃ BrF₃N₃.HCl); Calcd. (%): C: 48.62, H: 3.17, N: 9.45; Found (%): C: 48.49, H:3.11, N: 9.18.

EXAMPLE 40

N-(1-Naphthyl)-N'-(2-thiomethyl-5-trifluoromethylphenyl)guanidinehydrochloride (Formula I: hydrochloride salt of R=1-naphthyl, R¹ =R² ═H,R³ =SCH₃, R⁴ =CF₃, n=0).

white solid; mp 210° C.; ¹ H NMR (300 MHz, CD₃ OD): δ 8.11-8.14 (d, J=8Hz, 1, Ar--H), 7.98-8.01 (d, J=7 Hz; 2, Ar--H); 7.55-7.73 (m, 7, Ar--H);2.62 (3, s, S--CH₃); MS (EI): m/e 375 (M⁺ for free base); Anal.: (C₁₉H₁₆ F₃ N₃ S.HCl); Calcd. (%): C: 55.41, H: 4.16, N: 10.20; Found (%): C:55.27, H: 4.18, N: 10.90.

EXAMPLE 41

N-(1-Naphthyl)-N'-(2-methoxy-5-methylphenyl)guanidine hydrochloride(Formula I: hydrochloride salt of R=1-naphthyl, R¹ =R² ═H, R³ =OCH₃, R⁴=CH₃ ; n=0).

white solid; mp 194° C.; ¹ H NMR (300 MHz, CD₃ OD): δ 8.06-8.09 (d, J=8Hz, 1, Ar--H), 7.96-8.00 (m, 2, Ar--H); 7.52-7.69 (m, 4, Ar--H);7.14-7.20 (m, 2, Ar--H); 7.02-7.05 (dd, J=8.5 Hz; 1, Ar--H); 3.94 (s, 3,OCH₃); 2.29 (3, s, Ar--CH₃); Anal.: (C₁₉ H₁₉ N₃ O.HCl); Calcd. (%): C:66.76, H: 5.90, N: 12.29; Found (%): C: 66.25, H: 5.89, N: 12.23.

EXAMPLE 42

N-(1-Naphthyl)-N'-(2-chloro-5-ethylphenyl)guanidine hydrochloride(Formula I: hydrochloride salt of R=1-naphthyl, R¹ =R² ═H, R³ =Cl, R⁴=CH₂ CH₃, n=0).

white solid; mp 154° C.; ¹ H NMR (300 MHz, CD₃ OD): δ 8.07-8.10 (d, J=9Hz, 1, Ar--H), 7.97-8.01 (m, 2, Ar--H); 7.57-7.69 (m, 4, Ar--H);7.47-7.50 (d, J=8 Hz, 1, Ar--H); 7.13-7.35 (m, 2, Ar--H); 2.63-2.71 (q,J=7.5 Hz, 2, CH₂); 1.21-1.26 (t, J=8 Hz, 3, CH₃); MS (EI): m/e 324 (M⁺for free base).

EXAMPLE 43

N-(1-Naphthyl)-N'-(2-chloro-5-ethylphenyl)-N'-methylguanidinehydrochloride (Formula I: hydrochloride salt of R=1-naphthyl, R¹ =H, R²=CH₃, R³ =Cl, R⁴ =CH₂ CH₃, n=0).

white solid; mp 233° C.; ¹ H NMR (300 MHz, CD₃ OD): δ 7.97-8.02 (m, 3,Ar--H), 7.52-7.63 (m, 6, Ar--H); 7.31-7.34 (d, J=8 Hz, 1, Ar--H); 3.51(br s, 3, N--CH₃); 2.67-2.74 (q, J=7.5 Hz, 2, CH₂); 1.24-1.29 (t, J=8Hz, 3, CH₃); MS (EI): m/e 338 (M⁺ for free base); Anal.: (C₂₀ H₂₀ClN₃.HCl); Calcd. (%): C: 64.18, H: 5.65, N: 11.23; Found (%): C: 63.96,H: 5.83, N: 11.25.

EXAMPLE 44

N-(1-Naphthyl)-N'-(2-bromo-5-ethylphenyl)guanidine hydrochloride(Formula I: hydrochloride salt of R=1-naphthyl, R¹ =R² ═H, R³ =Br, R⁴=CH₂ CH₃, n=0).

white solid; TLC: R_(f) =0.5 (10% MeOH/CH₂ Cl₂); ¹ H NMR (300 MHz, CD₃OD): δ 8.09-7.22 (m, 10H, Ar--H), 2.67 (q, J=7.5 Hz, 2H, CH₂), 1.24 (t,J=7.5 Hz, 3H, CH₃).

EXAMPLE 45

N-(1-Naphthyl)-N'-(2-fluoro-5-ethylphenyl)guanidine hydrochloride(Formula I: hydrochloride salt of R=1-naphthyl, R¹ =R² ═H, R³ =F, R⁴=CH₂ CH₃, n=0).

white solid; TLC: R_(f) =0.5 (10% MeOH/CH₂ Cl₂); ¹ H NMR (300 MHz, CD₃OD): δ 8.05-7.19 (m, 10H, Ar--H), 2.65 (q, J=7.5 Hz, 2H, CH₂), 1.23 (t,J=7.5 Hz, 3H, CH₃).

EXAMPLE 46

N-(1-Naphthyl)-N'-(2-bromo-5-ethylphenyl)guanidine hydrochloride(Formula I: hydrochloride salt of R=1-naphthyl, R¹ =R² ═H, R³ =Br, R⁴=CH₂ CH₃, n=0).

white solid; TLC: R_(f) =0.5 (10% MeOH/CH₂ Cl₂); mp: 145-146° C.; ¹ HNMR (300 MHz, CD₃ OD): δ 8.09-7.22 (m, 10H, Ar--H), 2.67 (q, J=7.5 Hz,2H, CH₂), 1.24 (t, J=7.5 Hz, 3H, CH₃); MS (EI): m/e 367 (M⁺ for freebase).

EXAMPLE 47

N-(1-Naphthyl)-N'-(2-fluoro-5-ethylphenyl)guanidine hydrochloride(Formula I: hydrochloride salt of R=1-naphthyl, R¹ =R² ═H, R³ =F, R⁴=CH₂ CH₃, n=0).

white solid; TLC: R_(f) =0.5 (10% MeOH/CH₂ Cl₂); mp: 100-101° C.; ¹ HNMR (300 MHz, CD₃ OD): δ 8.05-7.19 (m, 10H, Ar--H), 2.65 (q, J=7.5 Hz,2H, CH₂), 1.23 (t, J=7.5 Hz, 3H, CH₃); MS (EI): m/e 307.1 (M⁺ for thefree base); Anal.: (C₁₉ H₁₈ FN₃.HCl); Calcd. (%): C: 66.37, H: 5.57, H:12.22; Found (%): C: 66.21, H: 5.50, N: 12.17.

EXAMPLE 48

N-(8-Quinolinyl)-N'-(2-chloro-5-methylphenyl)guanidine hydrochloride(Formula I: hydrochloride salt of R=8-quinolinyl, R¹ =R² ═H, R³ =Cl, R⁴=CH₃, n=0).

yellowish solid; mp 150° C.; ¹ H NMR (300 MHz, CD₃ OD): δ 8.98-8.00 (dd,1, Ar--H), 8.40-8.44 (dd, 1, Ar--H); 7.93-7.96 (d, 1, Ar--H); 7.82-7.84(d, 1, Ar--H); 7.61-7.68 (m, 2, Ar--H); 7.38-7.44 (m, 3, Ar--H);7.21-7.22 (d, 1, Ar--H); 3.30 (s, 3, CH₃); MS (EI): m/e 310 (M⁺ for freebase).

EXAMPLE 49

N-(8-Quinolinyl)-N'-(2-chloro-5-ethylphenyl)guanidine hydrochloride(Formula I: hydrochloride salt of R=8-quinolinyl, R¹ =R² ═H, R³ =Cl, R⁴=CH₂ CH₃, n=0).

brown solid; mp 167° C.; ¹ H NMR (300 MHz, CD₃ OD): δ 8.40-9.25 (m, 2,Ar--H), 7.27-8.34 (m, 7, Ar--H); 2.65-2.72 (q, 2, CH₂); 1.22-1.27 (t, 3,CH₃); MS (EI): m/e 324 (M⁺ for free base).

EXAMPLE 50

N-(3-Ethylphenyl)-N-methyl-N'-(2,4,5-trichlorophenyl)guanidinehydrochloride (Formula I: hydrochloride salt of R=3-ethylphenyl, R¹=CH₃, R² =H, R³ =R⁴ ═Cl, R⁵ =4-Cl, n=1).

white solid; TLC: R_(f) =0.3 (10% MeOH/CH₂ Cl₂); mp: 164-165° C.; ¹ HNMR (300 MHz, CD₃ OD): δ 7.79-7.23 (m, 6H, Ar--H), 3.49 (s, 3H, CH₃),2.70 (q, J=7.6 Hz, 2H, CH₂), 1.26 (t, J=7.6 Hz, 3H, CH₃); MS (EI): m/e335.0 (M⁺ for the free base); Anal.: (C₁₆ H₁₆ Cl₃ N₃.HCl.1/2H₂ O);Calcd. (%): C: 47.78, H: 4.51, N: 10.45; Found (%): C: 47.93, H: 4.63,N: 10.33.

EXAMPLE 51

N-(3-Ethylphenyl)-N'-(2,4,5-trichlorophenyl)guanidine hydrochloride(Formula I: hydrochloride salt of R=3-ethylphenyl, R¹ =R² ═H, R³ =R⁴═Cl, R⁵ =4-Cl, n=1).

white solid; TLC: R_(f) =0.4 (10% MeOH/CH₂ Cl₂); mp: 82-83° C.; ¹ H NMR(300 MHz, CD₃ OD): δ 7.63-7.18 (m, 6H, Ar--H), 2.63 (q, J=7.6 Hz, 2H,CH₂), 1.22 (t, J=7.6 Hz, 3H, CH₃); MS (EI): m/e 341 (M⁺ for the freebase).

EXAMPLE 52

N-(1-Naphthyl)-N'-(2,4,5-trichlorophenyl)guanidine hydrochloride(Formula I: hydrochloride salt of R=1-naphthyl, R¹ =R² ═H, R³ =R⁴ ═Cl,R⁵ =4-Cl, n=1).

white solid; TLC: R_(f) =0.4 (10% MeOH/CH₂ Cl₂); mp: 238-239° C.; ¹ HNMR (300 MHz, CD₃ OD): δ 8.08-7.58 (m, 10H, Ar--H); MS (EI): m/e 363 (M⁺for the free base); Anal.: (C₁₇ H₁₂ Cl₃ N₃.HCl); Calcd. (%): C: 50.9, H:3.29, N: 10.48; Found (%): C: 51.11, H: 3.33, N: 10.63.

EXAMPLE 53

N-(3-Ethylphenyl)-N-methyl-N'-(2-bromo-5-methylthiophenyl)guanidinehydrochloride (Formula I: hydrochloride salt of R=3-ethylphenyl, R¹=CH₃, R² =H, R³ =Br, R⁴ =CH₃ S, n=0).

TLC: R_(f) =0.5 (SiO₂, CH₂ Cl₂ /MeOH=10/1); M.P.: 90-92° C.; ¹ H NMR(CD₃ OD): δ (ppm) 7.64-7.15 (m, Ar--H, 7H), 3.49 (s, CH₃, 3H), 2.70 (q,J=7.4 Hz, 2H, CH₂), 2.47 (s, SCH₃, 3H), 1.25 (t, J=7.5 Hz, 3H, CH₃); MS(EI): m/e 377 (M⁺ : C₁₇ H₂₀ N₃ Br₁ S₁); Anal. (C₁₇ H₂₀ N₃ Br₁ S₁.HCl);Calcd. (%): C: 49.23, H: 5.1, N: 10.13; Found (%) C: 49.30, H: 5.28, N:10.28.

EXAMPLE 54

N-(3-Methylthiophenyl)-N-methyl-N'-(2,5-dichlorophenyl)guanidinehydrochloride (Formula I: hydrochloride salt of R=3-methylthiophenyl, R¹=CH₃, R² =H, R³ =R⁴ ═Cl, n=0).

TLC: R_(f) =0.3 (10% MeOH/CH₂ Cl₂); MP: 200-201° C.; ¹ H NMR (300 MHz,CD₃ OD): δ (ppm) 7.55-7.15 (m, 7H, Ar--H), 3.49 (s, 3H, NCH₃), 2.52 (s,3H, SCH₃); MS (EI): m/e 339 (M⁺ for the free base); Anal. (C₁₅ H₁₅ Cl₂N₃ S.HCl); Calcd. (%): C: 47.82, H: 4.28, N: 11.15; Found (%): C: 47.66,H: 4.26, N: 11.34.

EXAMPLE 55

N-(3-Methylthiophenyl)-N-methyl-N'-(2,5-dibromophenyl)guanidinehydrochloride (Formula I: hydrochloride salt of R=3-methylthiophenyl, R¹=CH₃, R² =H, R³ =R⁴ ═Br, n=0).

TLC: R_(f) =0.4 (10% MeOH/CH₂ Cl₂); MP: 239-240° C.; ¹ H NMR: δ (ppm)7.70-7.20 (m, 7H, Ar--H), 3.49 (s, 3H, NCH₃), 2.53 (s, 3H, SCH₃); MS(EI): m/e 429 (M⁺ for the free base); Anal. (C₁₅ H₁₅ Br₂ N₃ S.HCl);Calcd. (%): C: 38.69, H: 3.46, N: 9.02; Found (%): C: 38.65, H: 3.60, N:8.98.

EXAMPLE 56

N-(3-Methylthiophenyl)-N-methyl-N'-(2-chloro-5-ethylphenyl)guanidinehydrochloride (Formula I: hydrochloride salt of R=3-methylthiophenyl, R¹=CH₃, R² =H, R³ =Cl, R⁴ =CH₂ CH₃, n=0).

white solid; TLC: R_(f) =0.3 (10% MeOH/CH₂ Cl₂); MP: 212-213° C.; ¹ HNMR (300 MHz, CD₃ OD): δ (ppm) 7.45-7.19 (m, 7H, Ar--H), 3.49 (s, 3H,CH₃), 2.68 (q, J=7.5 Hz, 2H, CH₂), 2.51 (s, 3H, SCH₃), 1.22 (t, J=7.5Hz, 3H, CH₃); MS (EI): m/e 333 (M⁺ for the free base); Anal. (C₁₇ H₂₀ClN₃ S.HCl); Calcd. (%): C: 55.14, H: 5.72, N: 11.35; Found (%): C:55.29, H: 5.81, N: 11.36.

EXAMPLE 57

N-(3-Methylthiophenyl)-N-methyl-N'-(2-chloro-5-methylthiophenyl)guanidinehydrochloride (Formula I: hydrochloride salt of R=3-methylthiophenyl, R¹=CH₃, R² =H, R³ =Cl, R⁴ =SCH₃, n=0).

TLC: R_(f) =0.25 (10% MeOH/CH₂ Cl₂); MP: 203-204° C.; ¹ H NMR (300 MHz,CD₃ OD): δ (ppm) 7.50-7.18 (m, 7H, Ar--H), 3.49 (s, 3H, CH₃), 2.52 (s,3H, SCH₃), 2.49 (s, 3H, SCH₃); MS (EI): m/e 351 (M⁺ for the free base);Anal. (C₁₆ H₁₈ ClN₃ S₂.HCl); Calcd. (%): C: 49.48, H: 4.93, N: 10.82;Found (%): C: 49.41, H: 5.07, N: 10.81.

EXAMPLE 58

N-(3-Methylthiophenyl)-N-methyl-N'-(2-bromo-5-methylthiophenyl)guanidine(Formula I: R=3-methylthiophenyl, R¹ =CH₃, R² =H, R³ =Br, R⁴ =SCH₃,n=0).

TLC: R_(f) =0.43 (SiO₂, CH₂ Cl₂ /MeOH=10/1); M.P.: 174-175° C.; ¹ H NMR(CD₃ OD): δ (ppm) 7.65-7.15 (m, Ar--H, 7H), 3.49 (s, CH₃, 3H), 2.52 (s,SCH₃, 3H), 2.49 (s, SCH₃, 3H); HRMS: 395.0120 (Calcd.: 395.0126 for C₁₆H₁₈ N₃ BrS₂); HPLC: 98.47%.

EXAMPLE 59

N-(3-Methylthiophenyl)-N-methyl-N'-(2-bromo-5-ethylphenyl)guanidinehydrochloride (Formula I: hydrochloride salt of R=3-methylthiophenyl, R¹=CH₃, R² =H, R³ =Br, R⁴ =CH₂ CH₃, n=0)

TLC: R_(f) =0.3 (10% MeOH/CH₂ Cl₂); MP: 199-200° C.; ¹ H NMR (300 MHz,CD₃ OD): δ (ppm) 7.65-7.15 (m, 7H, Ar--H), 3.49 (s, 3H, CH₃), 2.64 (q,J=7.5 Hz, 2H, CH₂), 2.52 (s, 3H, SCH₃), 1.23 (t, J=7.5 Hz, 3H, CH₃); MS(EI): m/e 378 (M⁺ for the free base); Anal. (C₁₇ H₂₀ BrN₃ S.HCl); Calcd.(%): C: 49.23, H: 5.10, N: 10.13; Found (%): C: 49.39, H: 5.01, N:10.02.

EXAMPLE 60

N-(3-Trifluoromethylphenyl)-N-methyl-N'-(2,5-dichlorophenyl)guanidinehydrochloride (Formula I: hydrochloride salt ofR=3-trifluoromethylphenyl, R¹ =CH₃, R² =H, R³ =R⁴ ═Cl, n=0).

TLC: R_(f) =0.3 (10% MeOH/CH₂ Cl₂); MP: 209-210° C.; ¹ H NMR: δ (ppm)7.86-7.39 (m, 7H, Ar--H); 3.54 (s, 3H, CH₃); MS (EI): m/e 361 (M⁺ forthe free base); Anal. (C₁₅ H₁₂ Cl₂ F₃ N₃.HCl); Calcd. (%): C: 45.19, H:3.29; N: 10.54; Found (%): C: 45.31, H: 3.50, N: 10.61.

EXAMPLE 61

N-(3-Trifluoromethylphenyl)-N-methyl-N'-(2,5-dibromophenyl)guanidinehydrochloride (Formula I: hydrochloride salt ofR=3-trifluoromethylphenyl, R¹ =CH₃, R² =H, R³ =R⁴ ═Br, n=0).

TLC: R_(f) =0.5 (10% MeOH/CH₂ Cl₂); MP: 233-234° C.; ¹ H NMR: δ (ppm)7.90-7.45 (m, 7H, Ar--H); 3.54 (s, 3H, CH₃); MS (EI): m/e 449 (M⁺ forthe free base); Anal. (C₁₅ H₁₂ Br₂ F₃ N₃.HCl); Calcd. (%): C: 36.93, H:2.69, N: 8.62; Found (%): C: 37.00, H: 2.70, N: 8.56.

EXAMPLE 62

N-(3-Trifluoromethylphenyl)-N-methyl-N'-(2-chloro-5-methylthiophenyl)guanidinehydrochloride (Formula I: hydrochloride salt ofR=3-trifluoromethylphenyl, R¹ =CH₃, R² =H, R³ =Cl, R⁴ =SCH₃, n=0).

TLC: R_(f) =0.3 (10% MeOH/CH₂ Cl₂); MP: 156-157° C.; ¹ H NMR (300 MHz,CD₃ OD): δ (ppm) 7.90-7.20 (m, 7H, Ar--H), 3.53 (s, 3H, CH₃), 2.49 (s,3H, SCH₃); MS (EI): m/e 373 (M⁺ for the free base); Anal. (C₁₆ H₁₅ ClF₃N₃ S₂.HCl); Calcd. (%): C: 46.84, H: 3.93, N: 10.24; Found (%): C:46.78, H: 4.07, N: 10.12.

EXAMPLE 63

N-(3-Trifluoromethylphenyl)-N-methyl-N'-(2-chloro-5-ethylphenyl)guanidinehydrochloride (Formula I: hydrochloride salt ofR=3-trifluoromethylphenyl, R¹ =CH₃, R² =H, R³ =Cl, R⁴ =CH₂ CH₃, n=0).

TLC: R_(f) =0.3 (10% MeOH/CH₂ Cl₂); MP: 164-165° C.; ¹ H NMR (300 MHz,CD₃ OD): δ (ppm) 7.83-7.19 (m, 7H, Ar--H), 3.53 (s, 3H, CH₃), 2.65 (q,J=7.5 Hz, 2H, CH₂), 1.22 (t, J=7.5 Hz, 3H, CH₃); MS (EI): m/e 355 (M⁺for the free base); Anal. (C₁₇ H₁₇ ClF₃ N₃.HCl); Calcd. (%): C: 52.06,H: 4.63, N: 10.71; Found (%): C: 52.14, H: 4.79, N: 10.66.

EXAMPLE 64

N-(3-Trifluoromethylphenyl)-N-methyl-N'-(2-bromo-5-methylthiophenyl)guanidinehydrochloride (Formula I: hydrochloride salt ofR=3-trifluoromethylphenyl, R¹ =CH₃, R² =H, R³ =Br, R⁴ =SCH₃, n=0).

TLC: R_(f) =0.5 (10% MeOH/CH₂ Cl₂); MP: 121-122° C.; ¹ H NMR (300 MHz,CD₃ OD): δ (ppm) 7.87-7.15 (m, 7H, Ar--H), 3.53 (s, 3H, CH₃), 2.49 (s,3H, CH₃); MS (EI): m/e 419 (M⁺ for the free base); Anal. (C₁₆ H₁₅ BrF₃N₃ S.HCl); Calcd. (%): C: 42.26, H: 3.5, N: 9.24; Found (%): C: 42.27,H: 3.70, N: 9.06.

EXAMPLE 65

N-(3-Trifluoromethylphenyl)-N-methyl-N'-(2-bromo-5-ethylphenyl)guanidinehydrochloride (Formula I: hydrochloride salt ofR=3-trifluoromethylphenyl, R¹ =CH₃, R² =H, R³ =Br, R⁴ =CH₂ CH₃, n=0).

TLC: R_(f) =0.5 (10% MeOH/CH₂ Cl₂); MP: 95-96° C.; ¹ H NMR (300 MHz, CD₃OD): δ (ppm) 7.70-6.75 (m, 7H, Ar--H), 3.47 (s, 3H, CH₃), 2.58 (q, J=7.5HZ, 2H, CH₂), 1.22 (t, J=7.5 Hz, 3H, CH₃); MS (EI): m/e 401 (M⁺ for thefree base); Anal. (C₁₇ H₁₇ BrF₃ N₃.HCl); Calcd. (%): C: 46.76, H: 4.15,N: 9.62; Found (%): C: 46.57, H: 4.43, N: 9.38.

EXAMPLE 66

N-(3-Bromophenyl)-N-methyl-N'-(2-chloro-5-methylthiophenyl)guanidinehydrochloride (Formula I: hydrochloride salt of R=3-bromophenyl, R¹=CH₃, R² =H, R³ =Cl, R⁴ =SCH₃, n=0).

TLC: R_(f) =0.5 (10% MeOH/CH₂ Cl₂); MP: 244-245° C.; ¹ H NMR (300 MHz,CD₃ OD): δ (ppm) 7.80-7.20 (m, 7H, Ar--H), 3.53 (s, 3H, CH₃), 2.49 (s,3H, SCH₃); MS (EI): m/e 385 (M⁺ for the free base); Anal. (C₁₅ H₁₅BrClN₃ S.HCl); Calcd. (%): C: 42.78, H: 3.83, N: 9.98; Found (%): C:42.85, H: 3.99, N: 9.80.

EXAMPLE 67

N-(3-Trifluoromethoxyphenyl)-N'-(2-bromo-5-ethylphenyl)-N-methylguanidinehydrochloride (Formula I: hydrochloride salt ofR=3-trifluoromethoxyphenyl, R¹ =CH₃, R² =H, R³ =Br, R⁴ =CH₂ CH₃, n=0).

TLC: R_(f) =0.36 (SiO₂, CH₂ Cl₂ /MeOH=10/1); MP: 74-75° C.; ¹ H NMR (CD₃OD): δ (ppm) 7.63-7.15 (m, Ar--H, 7H), 3.30 (s, CH₃, 3H), 2.64 (m, CH₂,2H), 1.23 (t, CH₃, J=7.45 Hz, 3H); MS (EI): m/e 416.0 (M⁺ : C₁₇ H₁₇ N₃BrOF₃); Anal. (C₁₇ H₁₇ N₃ BrOF₃.HCl); Calcd. (%): C: 45.10, H: 4.01, N:9.28; Found (%): C: 45.31, H: 4.15, N: 9.09.

EXAMPLE 68

N-(3-Trifluoromethoxyphenyl)-N'-(2,5-dibromophenyl)-N-methylguanidinehydrochloride (Formula I: hydrochloride salt ofR=3-trifluoromethoxyphenyl, R¹ =CH₃, R² =H, R³ =R⁴ ═Br, n=0).

TLC: R_(f) =0.55 (SiO₂, CH₂ Cl₂ /MeOH=10/1); MP: 188-189° C.; ¹ H NMR(CD₃ OD): δ (ppm) 7.80-7.40 (m, Ar--H, 7H), 3.52 (s, CH₃, 3H); MS (EI):m/e 467.80 (M⁺ : C₁₅ H₁₂ N₃ Br₂ OF₃); Anal. (C₁₅ H₁₂ N₃ Br₂ OF₃.HCl);Calcd. (%): C: 35.78, H: 2.60, N: 8.34; Found (%): C: 35.72, H: 2.75, N:8.26.

EXAMPLE 69

N-(3-Methylsulfonylphenyl)-N-methyl-N'-(2,5-dibromophenyl)guanidinehydrochloride (Formula II: hydrochloride salt ofR=3-methylsulfonylphenyl, R¹ =CH₃, R² =H, R³ =R⁴ ═Br, n=0).

TLC: R_(f) =0.47 (SiO₂, CH₂ Cl₂ /MeOH=10/1); MP: 245-246° C.; ¹ H NMR(CD₃ OD): δ (ppm) 8.15-7.45 (m, Ar--H, 7H), 3.56 (s, CH₃, 3H), 3.17 (s,CH₃, 3H); MS (EI): m/e 462 (M⁺ : C₁₅ H₁₅ N₃ Br₂ SO₂); Anal. (C₁₅ H₁₅ N₃Br₂ So₂.HCl); Calcd. (%): C: 36.20, H: 3.24, N: 8.44; found (%): C:35.98, H: 3.11, N: 8.36.

EXAMPLE 70

N-(3-Methylsulfinylphenyl)-N-methyl-N'-(2,5-dibromophenyl)guanidinehydrochloride (Formula II: hydrochloride salt ofR=3-methylsulfinylphenyl, R¹ =CH₃, R² =H, R³ =R⁴ ═Br, n=0).

TLC: R_(f) =0.52 (SiO₂, CH₂ Cl₂ /MeOH=10/1); MP: 169-170° C.; ¹ H NMR(CD₃ OD): δ (ppm) 7.90-7.45 (m, Ar--H, 7H), 3.55 (s, CH₃, 3H), 2.85 (s,CH₃, 3H); MS (EI): m/e 446 (M⁺ : C₁₅ H₁₅ N₃ Br₂ SO); Anal. (C₁₅ H₁₅ N₃Br₂ SO.HCl); Calcd. (%): C: 37.41, H: 3.35, N: 8.72; Found (%): C:37.15, H: 3.46, N: 8.38.

EXAMPLE 71

N-(3-lodophenyl)-N-methyl-N'-(2-chloro-5-methylthiophenyl)guanidinehydrochloride (Formula I: hydrochloride salt of R=iodophenyl, R¹ =CH₃,R₂ =H, R³ =Cl, R⁴ =SCH₃, n=0). M.P.: 61-63° C.

EXAMPLE 72

N-(2-Chloro-5-ethylphenyl)-N'-(3-iodophenyl)guanidine hydrochloride(Formula I: hydrochloride salt of R=3-iodophenyl, R¹ =R² ═H, R³ =Cl, R⁴=CH₂ CH₃, n=0).

white solid; mp 76-77° C.; R_(f) =0.28 (10:1 CHCl₃ /MeOH): ¹ H NMR (300MHz, CD₃ OD): δ (ppm) 7.76-7.78 (m, 1H, Ar--H), 7.52-7.56 (m, 1H,Ar--H), 7.39-7.42 (d, J=6 Hz, 1H, Ar--H), 7.31-7.36 (m, 1H, Ar--H),7.08-7.22 (m, 3H, Ar--H), 3.30 (q, 2H, CH₂), 1.20-1.30 lt, 3H, CH₃);MS(EI): m/e 400 (M⁺ for free base); Anal.: (C₁₅ H₁₆ Cl₂ 1N₃.HCl); Calcd.(%): C: 41.31, H: 3.70, N: 9.63; Found (%): c: 44.60, H: 3.96, N: 9.59.

EXAMPLE 73

N-(2-chloro-5-thiomethylphenyl)-N'-(3-iodophenyl)-N'-methylguanidinehydrochloride (Formula I: hydrochloride salt of R=3-iodophenyl, R¹ =CH₃,R² =H, R³ =Cl, R⁴ =SCH₃, n=0).

brown solid; mp 61-63° C.; R_(f) =0.24 (10:1) CHCl₃ /MeOH); ¹ H NMR (300MHz, CD₃ OD): δ 7.74-7.75 (3, 1H, Ar--H), 7.58-7.62 (dt, 1H, Ar--H),7.30-7.37 (m, 2H, Ar--H), 7.14-7.19 (t, 1H, Ar--H), 6.92-6.97 (m, 2H,Ar--H), 3.36 (s, 3H, N--CH₃), 2.46 (s, 3H, SCH3); MS (EI): m/e 432 (M⁺for free base); Anal. (C₁₅ H₁₅ ClN₃ S.HCl.Et₂ O); Calcd. (%): C: 40.76,H: 4.33, N: 8.20; Found (%): C: 44.37, H: 4.69, N: 8.58.

EXAMPLE 74 PCP Radioligand Binding Assays

PCP receptor binding assays were performed using rat brain membranes asthe source of receptors. The radioligand used to label PCP receptors was[³ H]MK-801.

Synthesis of [³ H]MK-801 and PCP receptor binding assay protocols aredescribed in J. F. W. Keana, et al., Life Sci., 43:965-973 (1988).Briefly, in the protocols, rat brain membranes were prepared and used asdescribed for "detergent-treated membranes" (see D. E. Murphy, et al.,J. Pharmacol. Exp. Ther., 240:778-784 (1987)), and stored at a proteinconcentration of 10 mg/ml at -70° C. No effect of storage (1 month) ofthe membranes at -70° C. on receptor number or affinity for [³ H]MK-801was observed.

For assays with rat membranes, the thawed membranes were incubated at 1mg/ml with 0.01% Triton X-100 for 15 minutes at 32° C., then washedthree times by centrifugation to reduce the endogenous amino acidconcentrations, and finally resuspended in buffer for assay. Glycine and1-glutamate were each added back to a final concentration of 1 μM tomaximally stimulate the [³ H]MK-801 binding. The assays contain 400 μlof membranes, and 50 μl of buffer or unlabelled drug.

For [³ H]MK-801 binding, 1 nm radioligand was incubated with 200 μg/mlof rat brain membranes for 4 hours at room temperature. All assays werestopped by rapid filtration under vacuum through Whatman GF/B glassfiber filters presoaked in 0.05% polyethyleneimine using a Brandel48-well cell harvester (Brandel, Gaithersburg, Md.). The filters werewashed three times with 5 ml of cold 5 mM tris-HCl, pH=7.4. Each filterwas suspended in 10 ml of Cytoscint (ICN Biomedicals, Costa Mesa,Calif.) and radioactivity was measured by liquid scintillationspectrometry at a counting efficiency of 50%. Nonspecific binding wasdefined as that remaining in the presence of 10 μM MK-801 or 100 μM PCP.

Saturation data were evaluated and IC₅₀ values were determined asdescribed by J. B. Fischer and A. Schonbrunn (J. Biol. Chem.,263:2808-2816 (1988)). K_(i) values are derived from the IC₅₀ values asdescribed by Cheng et al., Biochem. Pharmacol., 22:3099-3108 (1973).

Results of the assay are shown in Table I which follows Example 75below, wherein the general formula of the tested compounds (i.e.,compounds identified as compound nos. 1-83) is shown at the top of TableI with the particular substituent groups of each compound specifiedwithin the Table.

EXAMPLE 75 Sigma Receptor Binding Assay

Methods.

Sigma receptor binding assays using guinea pig brain membranehomogenates and the radioligand [³ H]DTG were conducted as described byE. Weber, et al., P.N.A.S. (USA), 83:8784-8788 (1986). Briefly, frozenwhole guinea-pig brains (Biotrol, Indianapolis, Ind.) were homogenizedin 10 volumes (w/v) of ice-cold 320 mM sucrose using a Brinkmanpolytron. The homogenate was centrifuged at 1,000×g for 20 minutes at 4°C. The supernatant was centrifuged at 20,000×g for 20 minutes at 4° C.The resulting pellet was resuspended in 10 initial volumes of 50 mMTris/HCl buffer at pH 7.4 and centrifuged at 20,000×g for 20 minutes at4° C. The resulting pellet was resuspended in 5 initial volumes ice-cold50 mM Tris/HCl (pH 7.4), and the final volume was adjusted to yield aprotein concentration of 3 mg/ml. Aliquots of 20-ml were stored at -70°C. until used, with no detectable loss of binding.

For [³ H]DTG binding assays, the frozen membrane suspensions were thawedand diluted 1:3 in 50 mM Tris/HCl (pH 7.4). To 12×75 mm polystyrene testtubes were added 0.8 ml of diluted membrane suspension, 0.1 ml of [³H]DTG (Dupont/NEN) to yield a final concentration of 1.4 nM, and 0.1 mlof unlabelled drugs or buffer. The protein concentration in the 1-mlfinal incubation volume was 800 μg/ml, corresponding to 32 mg of braintissue (original wet weight) and to a tissue concentration within thelinear range for specific binding. Non-specific binding was defined asthat remaining in the presence of 10 μM haloperidol. Incubations wereterminated after 90 minutes at room temperature by addition of 4 ml ofice-cold 50 mM Tris/HCl (pH 7.4) and rapid filtration of the membranesuspension through Whatman GF/B glass-fiber filters under vacuum, usinga 48-well cell harvester (Brandel). The filters were washed 2 times with4 ml of 50 mM Tris/HCl (pH 7.4). Each filter was suspended in 10 mlCytoscint (ICI), and radioactivity was measured by liquid scintillationspectrometry at a counting efficiency of approximately 50%. IC₅₀ valueswere determined by non-linear regression analysis. The results are shownin Table I below for each of the tested compounds of the specifiedstructure. In Table I, the designation "NT" indicates the compound wasnot tested in the specified assay.

                                      TABLE I                                     __________________________________________________________________________     ##STR7##                                                                                                 [.sup.3 H-MK801]                                  Compd.                      IC.sub.50                                                                        K.sub.1                                                                          [.sup.3 H-DTG]                              No. R        R.sup.1                                                                          R.sup.2                                                                          R.sup.3                                                                           R.sup.4                                                                            (nM)                                                                             (nM)                                                                             IC.sub.50 (nM)                              __________________________________________________________________________    1   3-ethylphenyl                                                                          H  H  Cl  Cl   88 67.7                                                                             11.8                                        2   3-ethylphenyl                                                                          H  H  Br  Br   87.5                                                                             67.3                                                                             18.2                                        3   3-ethylphenyl                                                                          H  H  H   Cl   146                                                                              112                                                                              15.5                                        4   3-ethylphenyl                                                                          H  H  Br  CF.sub.3                                                                           86.9                                                                             66.8                                                                             10.3                                        5   3-ethylphenyl                                                                          H  H  F   CF.sub.3                                                                           98.9                                                                             76.0                                                                             14.8                                        6   3-ethylphenyl                                                                          H  H  Cl  CF.sub.3                                                                           57.1                                                                             43.9                                                                             14.2                                        7   3-ethylphenyl                                                                          H  H  Cl  CH.sub.3                                                                           100                                                                              76.9                                                                             30.6                                        8   3-ethylphenyl                                                                          H  H  Cl  CH.sub.2 CH.sub.3                                                                  45.2                                                                             34.7                                                                             2.04                                        9   3-ethylphenyl                                                                          H  H  H   CH.sub.2 CH.sub.3                                                                  168                                                                              129                                                                              8.0                                         10  3-ethylphenyl                                                                          CH.sub.3                                                                         H  Cl  Cl   84.6                                                                             65.0                                                                             28.5                                        11  3-ethylphenyl                                                                          CH.sub.3                                                                         H  Br  Br   47.6                                                                             36.6                                                                             40.2                                        12  3-ethylphenyl                                                                          CH.sub.3                                                                         H  H   Cl   646                                                                              497                                                                              43.5                                        13  3-ethylphenyl                                                                          CH.sub.3                                                                         H  Br  CF.sub.3                                                                           102                                                                              78.4                                                                             208                                         14  3-ethylphenyl                                                                          CH.sub.3                                                                         H  F   CF.sub.3                                                                           252                                                                              194                                                                              85                                          15  3-ethylphenyl                                                                          CH.sub.3                                                                         H  Cl  CF.sub.3                                                                           131                                                                              101                                                                              120                                         16  3-ethylphenyl                                                                          CH.sub.3                                                                         H  Cl  CH.sub.3                                                                           101                                                                              77.6                                                                             45.3                                        17  3-ethylphenyl                                                                          CH.sub.3                                                                         H  Cl  CH.sub.2 CH.sub.3                                                                  53 40.7                                                                             115                                         18  3-ethylphenyl                                                                          CH.sub.3                                                                         H  H   CH.sub.2 CH.sub.3                                                                  213                                                                              164                                                                              81.8                                        19  3-ethylphenyl                                                                          CH.sub.3                                                                         H  H   Br   105                                                                              80.7                                                                             40                                          20  3-ethylphenyl                                                                          CH.sub.3                                                                         H  F   CH.sub.2 CH.sub.3                                                                  126                                                                              96.9                                                                             112.5                                       21  3-ethylphenyl                                                                          H  H  F   CH.sub.2 CH.sub.3                                                                  64.8                                                                             49.8                                                                             7.4                                         22  3-ethylphenyl                                                                          CH.sub.3                                                                         H  Br  CH.sub.2 CH.sub.3                                                                  16.7                                                                             12.8                                                                             203                                         23  3-ethylphenyl                                                                          H  H  Br  CH.sub.2 CH.sub.3                                                                  38.3                                                                             24.9                                                                             5.07                                        24  3-ethylphenyl                                                                          CH.sub.3                                                                         H  Cl  SCH.sub.3                                                                          6.7                                                                              5.1                                                                              309.5                                       25  3-ethylphenyl                                                                          H  H  Cl  SCH.sub.3                                                                          15.4                                                                             11.8                                                                             15.8                                        26  3-ethylphenyl                                                                          CH.sub.3                                                                         CH.sub.3                                                                         Cl  Cl   93.7                                                                             72.0                                                                             39.3                                        27  3-ethylphenyl                                                                          CH.sub.3                                                                         CH.sub.3                                                                         Br  Br   35.5                                                                             27.3                                                                             380                                         28  3-ethylphenyl                                                                          CH.sub.3                                                                         CH.sub.3                                                                         Cl  CH.sub.2 CH.sub.3                                                                  145                                                                              112                                                                              240.5                                       29  2-chloro-5-                                                                            H  H  Cl  CH.sub.3                                                                           54.7                                                                             42.1                                                                             36.1                                            ethylphenyl                                                               30  2-chloro-5-                                                                            H  H  Br  Br   66.4                                                                             51.0                                                                             186                                             ethylphenyl                                                               31  1-naphthyl                                                                             H  H  Cl  Cl   41 31.5                                                                             25                                          32  1-naphthyl                                                                             H  H  Br  Br   48.6                                                                             37.3                                                                             37.6                                        33  1-naphthyl                                                                             H  H  CH.sub.3                                                                          CH.sub.3                                                                           79.2                                                                             60.9                                                                             27.4                                        34  1-naphthyl                                                                             H  H  F   CH.sub.3                                                                           86 66.1                                                                             69                                          35  1-naphthyl                                                                             H  H  Cl  CH.sub.3                                                                           31.2                                                                             24.0                                                                             43                                          36  1-naphthyl                                                                             H  H  OCH.sub.3                                                                         CH.sub.3                                                                           61.5                                                                             47.3                                                                             161                                         37  1-naphthyl                                                                             H  H  H   Cl   371                                                                              285                                                                              33                                          38  1-naphthyl                                                                             H  H  H   CH.sub.3                                                                           192                                                                              148                                                                              75                                          39  1-naphthyl                                                                             H  H  F   CF.sub.3                                                                           38.4                                                                             29.5                                                                             79.4                                        40  1-naphthyl                                                                             H  H  Cl  CF.sub.3                                                                           38.6                                                                             29.6                                                                             52.5                                        41  1-naphthyl                                                                             H  H  Br  CF.sub.3                                                                           51.1                                                                             39.3                                                                             49.6                                        42  1-naphthyl                                                                             H  H  SCH.sub.3                                                                         CF.sub.3                                                                           170                                                                              131                                                                              418                                         43  1-naphthyl                                                                             H  H  H   CF.sub.3                                                                           129                                                                              99.2                                                                             238                                         44  1-naphthyl                                                                             H  H  Cl  CH.sub.2 CH.sub.2                                                                  20.6                                                                             15.8                                                                             4.94                                        45  1-naphthyl                                                                             H  H  H   CH.sub.2 CH.sub.3                                                                  39 30.0                                                                             53.8                                        46  1-naphthyl                                                                             H  H  Cl  SCH.sub.3                                                                          43 33.2                                                                             25.4                                        47  1-naphthyl                                                                             H  H  H   SCH.sub.3                                                                          124                                                                              95.3                                                                             27                                          48  8-quinolinyl                                                                           H  H  Cl  CH.sub.3                                                                           32 24.4                                                                             989                                         49  8-quinolinyl                                                                           H  H  Cl  CH.sub.2 CH.sub.3                                                                  4.2                                                                              3.2                                                                              322                                         50  1-naphthyl                                                                             H  CH.sub.3                                                                         Cl  Cl   62 47.6                                                                             1318                                        51  1-naphthyl                                                                             H  CH.sub.3                                                                         Br  Br   65 49.9                                                                             1250                                        52  1-naphthyl                                                                             H  CH.sub.3                                                                         H   Cl   107                                                                              82.3                                                                             2982                                        53  1-naphthyl                                                                             H  CH.sub.3                                                                         H   Br   54 41.6                                                                             2759                                        54  1-naphthyl                                                                             H  CH.sub.3                                                                         CH.sub.3                                                                          CH.sub.3                                                                           79 60.8                                                                             1554                                        55  1-naphthyl                                                                             H  CH.sub.3                                                                         Cl  CH.sub.3                                                                           41 31.6                                                                             2425                                        56  1-naphthyl                                                                             H  CH.sub.3                                                                         H   CH.sub.3                                                                           85 65.4                                                                             1262                                        57  1-naphthyl                                                                             H  CH.sub.3                                                                         Cl  CH.sub.2 CH.sub.3                                                                  32.8                                                                             25.2                                                                             136                                         58  1-naphthyl                                                                             H  CH.sub.3                                                                         H   CH.sub.2 CH.sub.3                                                                  37.5                                                                             28.8                                                                             2635                                        59  3-ethylphenyl                                                                          CH.sub.3                                                                         H  Br  CH.sub.3                                                                           3.19                                                                             2.45                                                                             240                                         60  3-methylthiophenyl                                                                     CH.sub.3                                                                         H  Cl  SCH.sub.3                                                                          2.43                                                                             1.84                                                                             480                                         61  3-methylthiophenyl                                                                     CH.sub.3                                                                         H  Cl  CH.sub.2 CH.sub.3                                                                  12.6                                                                             9.69                                                                             178                                         62  3-methylthiophenyl                                                                     CH.sub.3                                                                         H  Cl  Cl   59.3                                                                             45.6                                                                             130                                         63  3-methylthiophenyl                                                                     CH.sub.3                                                                         H  Br  SCH.sub.3                                                                          2.15                                                                             1.65                                                                             NT                                          64  3-methylthiophenyl                                                                     CH.sub.3                                                                         H  Br  CH.sub.2 CH.sub.3                                                                  5.09                                                                             3.92                                                                             180                                         65  3-methylthiophenyl                                                                     CH.sub.3                                                                         H  Br  Br   5.38                                                                             4.13                                                                             113                                         66  3-trifluoromethyl-                                                                     CH.sub.3                                                                         H  Cl  SCH.sub.2                                                                          8.47                                                                             6.92                                                                             421                                             phenyl                                                                    67  3-trifluoromethyl-                                                                     CH.sub.3                                                                         H  Cl  CH.sub.2 CH.sub.3                                                                  77.0                                                                             59.2                                                                             200                                             phenyl                                                                    68  3-trifluoromethyl-                                                                     CH.sub.3                                                                         H  Cl  Cl   201                                                                              155                                                                              110                                             phenyl                                                                    69  3-trifluoromethyl-                                                                     CH.sub.3                                                                         H  Br  SCH.sub.3                                                                          5.55                                                                             4.27                                                                             631                                             phenyl                                                                    70  3-trifluoromethyl-                                                                     CH.sub.3                                                                         H  Br  CH.sub.2 CH.sub.3                                                                  20.4                                                                             15.7                                                                             166                                             phenyl                                                                    71  3-trifluoromethyl-                                                                     CH.sub.3                                                                         H  Br  Br   34.0                                                                             26.1                                                                             224                                             phenyl                                                                    72  3-bromophenyl                                                                          CH.sub.3                                                                         H  Cl  SCH.sub.3                                                                          4.65                                                                             3.58                                                                             NT                                          73  3-trifluoro-                                                                           CH.sub.3                                                                         H  Br  Br   25.6                                                                             19.7                                                                             NT                                              methoxyphenyl                                                             74  3-trifluoro-                                                                           CH.sub.3                                                                         H  Br  CH.sub.2 CH.sub.3                                                                  16.0                                                                             12.3                                                                             NT                                              methoxyphenyl                                                             75  3-methyl-                                                                              CH.sub.3                                                                         H  Br  Br   530                                                                              408                                                                              NT                                              sulfonylphenyl                                                            76  3-methyl-                                                                              CH.sub.3                                                                         H  Br  Br   322                                                                              248                                                                              NT                                              sulfinylphenyl                                                            77  iodophenyl                                                                             CH.sub.3                                                                         H  Cl  SCH.sub.3                                                                          2.11                                                                             1.62                                                                             NT                                          78  3-iodophenyl                                                                           H  H  Cl  CH.sub.2 CH.sub.3                                                                  13.7                                                                             10.5                                                                             NT                                          79  8-quinolinyl                                                                           CH.sub.3                                                                         H  Cl  SCH.sub.3                                                                          22.3                                                                             17 542                                         __________________________________________________________________________

EXAMPLE 76

In vivo assay for protection against NMDA-induced excitotoxic damage tothe central nervous system.

The in vivo potency of compounds of the present invention is exemplifiedby data summarized in Table II and obtained pursuant to the followingprotocol. Day 7 neonatal rats were anesthetized with metophaneinhalation anesthetic for 4-6 minutes, inserted into a stereotaxicapparatus and injected intrastriatally with 0.5 μl of 50 mM NMDA(N-methyl-D-aspartate). 15 minutes after the NMDA injection, the ratpups were injected intraperitoneally with 10, 30 or 60 μmol/kg of theNMDA antagonist of the structure specified in Table II. Animals werereturned to their mother and watched for signs of distress (e.g.,respiratory depression). After five days, the animals were anesthetizedwith CO₂ and then decapitated; their brains were removed and weighed todetermine the degree of neuroprotection. Because NMDA injection resultsin a retardation of brain growth (including necrosis), effects can bemeasured gravimetrically in terms of the weights of injected andnon-injected hemispheres. Two groups of rat pups were used at each ofthree doses of a compound to generate a neuroprotection dose-responsecurve. The chemical structure of each of the tested compounds isspecified below with the general formula of the compounds shown at thetop of Table II with particular substituent groups specified within thatTable. Table II discloses 1) the ED₈₀ for each tested compound, i.e.,the dose of a compound that provides 80% of the maximum protectionagainst damage to the central nervous system; and 2) the percent (%)maximum protection against damage to the central nervous system providedby the indicated dose expressed as μmol per kilogram bodyweight of thetest subject.

                                      TABLE II                                    __________________________________________________________________________     ##STR8##                                                                                                     % maximum                                     Cmpd.                      ED80 protection per                                No.  R      R.sub.1                                                                           R.sub.2                                                                           R.sub.3                                                                           R.sub.4                                                                          μmol/kg                                                                         dose (μmol/kg)                             __________________________________________________________________________    1    3-ethylphenyl                                                                        CH.sub.3                                                                          H   Cl  Cl 36.4 88.8 @ 60                                     2    3-ethylphenyl                                                                        CH.sub.3                                                                          H   Br  Br 13.4 93.8 @ 60                                     3    3-ethylphenyl                                                                        H   H   F   CF.sub.3                                                                         15.2 76.6 @ 60                                     4    3-ethylphenyl                                                                        CH.sub.3                                                                          H   Cl  C.sub.2 H.sub.5                                                                  19.8 77.8 @ 60                                     5    1-naphthyl                                                                           H   CH.sub.3                                                                          Cl  C.sub.2 H.sub.5                                                                  22.3 92.2 @ 60                                     6    1-naphthyl                                                                           H   CH.sub.3                                                                          Br  Br 26.9 85.7 @ 60                                     7    1-naphthyl                                                                           H   CH.sub.3                                                                          CH.sub.3                                                                          CH.sub.3                                                                         22.5 86.0 @ 30                                     8    1-naphthyl                                                                           H   H   F   CF.sub.3                                                                         28.8 96.0 @ 60                                     9    1-naphthyl                                                                           H   H   Cl  SCH.sub.3                                                                        10.8 92.7 @ 60                                     10   1-naphthyl                                                                           H   H   Cl  CH.sub.3                                                                         45.8 96.4 @ 60                                     11   8-quinolyl                                                                           H   H   Cl  C.sub.2 H.sub.5                                                                  14.2 94.5 @ 30                                     __________________________________________________________________________

This invention has been described in detail with reference to preferredembodiments thereof. However, it will be appreciated that those skilledin the art, upon consideration of this disclosure, may makemodifications and improvements within the spirit and scope of theinvention.

What is claimed is:
 1. A method of inhibiting NMDA receptor-ion channelrelated neurotoxicity or susceptible thereto in a mammal exhibiting suchneurotoxicity comprising administering to the mammal an effective amountof a compound of the following formula I: ##STR9## wherein R issubstituted or unsubstituted carbocyclic aryl, substituted orunsubstituted aralkyl, or a substituted or unsubstituted heteroaromaticor heterocyclic group having 1 to 3 rings, 3 to 8 ring members in eachring and 1 to 3 heteroatoms;R¹ and R² are each independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted alkoxy, substituted or unsubstituted alkylthio,substituted or unsubstituted aminoalkyl, substituted or unsubstitutedcarbocyclic aryl, substituted or unsubstituted aralkyl, or a substitutedor unsubstituted heteroaromatic or heteroalicyclic group having 1 to 3rings, 3 to 8 ring members in each ring and 1 to 3 hetero atoms; R³, R⁴,and each R⁵ substituent are each independently halogen, azido,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted alkoxy, substituted or unsubstituted alkylthio,substituted or unsubstituted aminoalkyl, substituted or unsubstitutedcarbocyclic aryl, or substituted or unsubstituted aralkyl; n is aninteger of from 0-3; or a pharmaceutically acceptable salt thereof, withthe exclusion of N-(2,4-di-iodo-5-hydroxyphenyl)-N'-(2-tolyl)-guanidineand N-(2-methoxy-5-ethylphenyl)-N'-naphthylguanidine.
 2. The method ofclaim 1 wherein said neurotoxicity is caused by excessive release ofendogenous glutamate following the occurrence of hypoxia, hypoglycemia,brain or spinal chord ischemia, or brain or spinal chord trauma.
 3. Amethod of treating nerve cell death, stroke, heart attack, brain orspinal cord trauma, brain or spinal cord ischemia or heart attackcomprising administering to a mammal in need of such treatment aneffective amount of a compound of the following formula I: ##STR10##wherein R is substituted or unsubstituted carbocyclic aryl, substitutedor unsubstituted aralkyl, or a substituted or unsubstitutedheteroaromatic or heterocyclic group having 1 to 3 rings, 3 to 8 ringmembers in each ring and 1 to 3 heteroatoms;R¹ and R² are eachindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubsuituted alkoxy, substituted or unsubstitutedalkylthio, substituted or unsubstituted aminoalkyl, substituted orunsubstituted carbocyclic aryl, substituted or unsubstituted aralkyl, ora substituted or unsubstituted heteroaromatic or heteroalicyclic grouphaving 1 to 3 rings, 3 to 8 ring members in each ring and 1 to 3 heteroatoms; R³, R⁴, and each R⁵ substituent are each independently halogen,azido, substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkyl, substituted orunsubstituted alkoxy, substituted or unsubstituted alkyithio,substituted or unsubstituted aminoalkyl, substituted or unsubstitutedcarbocyclic aryl, or substituted or unsubstituted aralkyl; n is aninteger of from 0-3; or a pharmaceutically acceptable salt thereof, withthe exclusion of N-(2,4-di-iodo-5-hydroxyphenyl)-N'-(2-tolyl)-guanidineand N-(2-methoxy-5-ethylphenyl)-N'-naphthylguanidine.
 4. A method ofinhibiting NMDA receptor-ion channel related neurotoxicity orsusceptible thereto in a mammal exhibiting such neurotoxicity comprisingadministering to the mammal an effective amount of a compound of thefollowing formula II: ##STR11## wherein R is substituted orunsubstituted carbocyclic aryl, substituted or unsubstituted aralkyl, ora substituted or unsubstituted heteroaromatic or heterocyclic grouphaving 1 to 3 rings, 3 to 8 ring members in each ring and 1 to 3heteroatoms;R¹ and R² are each independently hydrogen, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted alkoxy,substituted or unsubstituted alkylthio, substituted or unsubstitutedalkylsulfinyl, substituted or unsubstituted alkylsulfonyl, substitutedor unsubstituted aminoalkyl, substituted or unsubstituted carbocyclicaryl, substituted or unsubstituted aralkyl, or a substituted orunsubstituted heteroaromatic or heteroalicyclic group having 1 to 3rings, 3 to 8 ring members in each ring and 1 to 3 hetero atoms; R³, R⁴,and each R⁵ substituent are each independently halogen, hydroxyl, azido,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted alkoxy, substituted or unsubstituted alkylthio,substituted or unsubstituted alkylsulfinyl, substituted or unsubstitutedalkylsulfonyl, substituted or unsubstituted aminoalkyl, substituted orunsubstituted carbocyclic aryl, or substituted or unsubstituted aralkyl;and with at least one of R, R¹, R², R³, R⁴ and R⁵ being alkylsulfinyl oralkylsulfonyl; n is an integer of from 0-3; or a pharmaceuticallyacceptable salt thereof.
 5. A method of treating nerve cell death,stroke, heart attack, brain or spinal cord trauma, brain or spinal cordischemia or heart attack comprising administering to a mammal in need ofsuch treatment an effective amount of a compound of the followingformula II: ##STR12## wherein R is substituted or unsubstitutedcarbocyclic aryl, substituted or unsubstituted aralkyl, or a substitutedor unsubstituted heteroaromatic or heterocyclic group having 1 to 3rings, 3 to 8 ring members in each ring and 1 to 3 heteroatoms;R¹ and R²are each independently hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted alkoxy, substituted orunsubstituted alkylthio, substituted or unsubstituted allylsulfinyl,substituted or unsubstituted alkylsulfonyl, substituted or unsubstitutedaminoalkyl, substituted or unsubstituted carbocyclic aryl, substitutedor unsubstituted aralkyl, or a substituted or unsubstitutedheteroaromatic or heteroalicyclic group having 1 to 3 rings, 3 to 8 ringmembers in each ring and 1 to 3 hetero atoms; R³, R⁴, and each R⁵substituent are each independently halogen, hydroxyl, azido, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedalkoxy, substituted or unsubstituted alkylthio, substituted orunsubstituted alkylsulfinyl, substituted or unsubstituted alkylsulfonyl,substituted or unsubstituted aminoalkyl, substituted or unsubstitutedcarbocyclic aryl, or substituted or unsubstituted aralkyl; and with atleast one of R, R¹, R², R³, R⁴ and R⁵ being alkylsulfinyl oralkylsulfonyl; n is an integer of from 0-3; or a pharmaceuticallyacceptable salt thereof.
 6. A method of claim claim 3 wherein the mammalis suffering from stroke.
 7. A method of claim 3 wherein the mammal issuffering from brain or spinal cord trauma or brain or spinal cordischemia.
 8. A method of claim 3 wherein the mammal is suffering fromheart attack.
 9. A method of treating a mammal suffering from nerve celldegeneration resulting from hypoxia, hypoglycemia, brain or spinal cordischemia or brain or spinal cord trauma, comprising administering to themammal an effective amount of a compound of the following formula I:##STR13## wherein R is substituted or unsubstituted carbocyclic aryl,substituted or unsubstituted aralkyl, or a substituted or unsubstitutedheteroaromatic or heterocyclic group having 1 to 3 rings, 3 to 8 ringmembers in each ring and 1 to 3 heteroatoms;R¹ and R² are eachindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted alkoxy, substituted or unsubstitutedalkylthio, substituted or unsubstituted aminoalkyl, substituted orunsubstituted carbocyclic aryl, substituted or unsubstituted aralkyl, ora substituted or unsubstituted heteroaromatic or heteroalicyclic grouphaving 1 to 3 rings, 3 to 8 ring members in each ring and 1 to 3 heteroatoms; R³, R⁴, and each R⁵ substituent are each independently halogen,azido, substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted alkoxy, substituted or unsubstituted alkylthio,substituted or unsubstituted aminoalkyl, substituted or unsubstitutedcarbocyclic aryl, or substituted or unsubstituted aralkyl; n is aninteger of from 0-3; or a pharmaceutically acceptable salt thereof, withthe exclusion of N-(2,4-di-iodo-5-hydroxyphenyl)-N'-(2-tolyl)-guanidineand N-(2-methoxy-5-ethylphenyl)-N'-naphthylguanidine.
 10. A method oftreating a mammal undergoing surgery where neurological deficit is apotential complication, comprising administering to the mammal atreatment effective amount of the following formula I: ##STR14## whereinR is substituted or unsubstituted carbocyclic aryl, substituted orunsubstituted aralkyl, or a substituted or unsubstituted heteroaromaticor heterocyclic group having 1 to 3 rings, to 3 to 8 ring members ineach ring and 1 to 3 heteroatoms;R¹ and R² are each independentlyhydrogen, substituted or unsubstituted alkyl, substituted orunsubstituted alkenyl, substituted or unsubstituted alkynyl, substitutedor unsubstituted alkoxy, substituted or unsubstituted alkylthio,substituted or unsubstituted aminoalkyl, substituted or unsubstitutedcarbocyclic aryl, substituted or unsubstituted aralkyl, or a substitutedor unsubstituted heteroaromatic or heteroalicyclic group having 1 to 3rings, 3 to 8 ring members in each ring and 1 to 3 hetero atoms; R³, R⁴,and each R⁵ substituent are each independently halogen, hydroxyl, azido,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted alkoxy, substituted or unsubstituted alkylthio,substituted or unsubstituted aminoalkyl, substituted or unsubstitutedcarbocyclic aryl, or substituted or unsubstituted aralkyl; n is aninteger of from 0-3; or a pharrnaccutically acceptable salt thereof,with the exclusion ofN-(2,4-di-iodo-5-hydroxphenyl)-N'-(2-tolyl)-guanidine andN-(2-methoxy-5-ethylphenyl)-N'-naphthylguanidine.
 11. The method of anyone of claims 1, 3, 6, 7, 8 or 9 wherein the compound isN-(3-methylthiophenyl)-N-methyl-N'-(2-chloro-5-methylthiophenyl)guanidineor a pharmaceutically acceptable salt thereof.
 12. The method of any oneof claims 1, 3, 6, 7, 8 or 9 wherein the compound isN-(3-ethylphenyl)-N-methyl-N'-(2,5-dibromophenyl)guanidine or apharmaceutically acceptable salt thereof.
 13. A method of claim 1wherein both R and R² are hydrogen.
 14. A method of claim 1 wherein atleast two of R, R¹ and R² is other than hydrogen.
 15. The method ofclaim 1 or 3 wherein the compound is of the following Formula Ia:##STR15## wherein R and R² are each independently hydrogen, substitutedor unsubstituted alkyl, substituted or unsubstituted alkenyl,substituted or unsubstituted alkynyl, substituted or unsubstitutedalkoxy, substituted or unsubstituted alkylthio, substituted orunsubstituted aminoalkyl, substituted or unsubstituted carbocyclic aryl,substituted or unsubstituted aralkyl, or a substituted or unsubstitutedheteroaromatic or heteroalicyclic group having 1 to 3 rings, 3 to 8 ringmembers in each ring and 1 to 3 hetero atoms;R³, R⁴, each R⁵, R^(3'),R^(4'), and each R^(5') are each independently halogen, azido,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted alkoxy, substituted or unsubstituted alkylthio,substituted or unsubstituted aminoalkyl, substituted or unsubstitutedcarbocyclic aryl, or substituted or unsubstituted aralkyl; m and n areeach independently an integer of from 0 to 3; or a pharmaceuticallyacceptable salt thereof.
 16. The method of claim 1 or 3 wherein thecompound is of the following Formula Ib: ##STR16## wherein R issubstituted or unsubstituted carbocyclic aryl, substituted orunsubstituted aralkyl, or a substituted or unsubstituted heteroaromaticor heterocyclic group having 1 to 3 rings, 3 to 8 ring members in eachring and 1 to 3 heteroatoms;R¹ and R² are each independently hydrogen,substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted alkoxy, substituted or unsubstituted alkylthio,substituted or unsubstituted aminoalkyl, substituted or unsubstitutedcarbocyclic aryl, substituted or unsubstituted aralkyl, or a substitutedor unsubstituted heteroaromatic or heteroalicyclic group having 1 to 3rings, 3 to 8 ring members in each ring and 1 to 3 hetero atoms; R³ andR⁴ are each independently halogen, azido, substituted or unsubstitutedalkyl, substituted or unsubstituted alkenyl, substituted orunsubstituted alkynyl, substituted or unsubstituted alkoxy, substitutedor unsubstituted alkylthio, substituted or unsubstituted aminoalkyl,substituted or unsubstituted carbocyclic aryl, or substituted orunsubstituted aralkyl; or a pharmaceutically acceptable salt thereof.17. The method of any one of claims 1, 3, 6 or 9 wherein the compound isof the following Formula Ic: ##STR17## wherein R and R² are eachindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted alkoxy, substituted or unsubstitutedalkylthio, substituted or unsubstituted aminoalkyl, substituted orunsubstituted carbocyclic aryl, substituted or unsubstituted aralkyl, ora substituted or unsubstituted heteroaromatic or heterocyclic grouphaving 1 to 3 rings, 3 to 8 ring members in each ring and 1 to 3heteroatoms;R^(3'), R^(4'), R^(3") and each R^(5') substituent are eachindependently halogen, azido, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted alkoxy, substituted orunsubstituted alkylthio, substituted or unsubstituted aminoalkyl,substituted or substituted carbocyclic aryl, or substituted orunsubstituted aralkyl; n is an integer of from 0 to 3; or apharmaceutically acceptable salt thereof.
 18. A method of claim 17wherein both R and R² are hydrogen.
 19. A method of claim 17 wherein atleast one of R and R² is other than hydrogen.
 20. A method of claim 19wherein R and R² are hydrogen or alkyl having 1 to about 4 carbons. 21.A method of claim 17 wherein R is methyl, ethyl or propyl and R² ishydrogen.
 22. A method of claim 21 where R is methyl.
 23. A method ofclaim 17 wherein R^(3'), R^(4'), R^(5') and R^(3") are independentlyhalogen, azido, alkyl, halogenated alkyl, alkoxy, halogenated alkoxy oralkylthio.
 24. A method of claim 1 or 3 wherein the compoundis:N-(3-ethylphenyl)-N,N'-dimethyl-N'-(2,5-dichlorophenyl)guanidine;N-(3-ethylphenyl)-N-methyl-N'-(2,5-dichlorophenyl)guanidine;N-(3-ethylphenyl)-N'-(2,5-dichlorophenyl)-N'-methylguanidine;N-(3-ethylphenyl)-N'-(2,5-dichlorophenyl)guanidine;N-(3-ethylphenyl)-N-methyl-N'-(2,5-dibromophenyl)guanidine;N-(3-ethylphenyl)-N'-(2,5-dibromophenyl)-N'-methylguanidine;N-(3-ethylphenyl)-N'-(2,5-dibromophenyl)guanidine;N-(3-ethylphenyl)-N-methyl-N'-(2-chloro-5-trifluoromethylphenyl)guanidine;N-(3-ethylphenyl)-N'-(2-chloro-5-trifluoromethylphenyl)guanidine;N-(3-ethylphenyl)-N,N'-dimethyl-N'-(2-bromo-5-trifluoromethylphenyl)guanidine;N-(3-ethylphenyl)-N-methyl-N'-(2-bromo-5-trifluoromethylphenyl)guanidine;N-(3-ethylphenyl)-N'-(2-bromo-5-trifluoromethylphenyl)guanidine;N-(3-ethylphenyl)-N-methyl-N'-(2-fluoro-5-trifluoromethylphenyl)guanidine;N-(3-ethylphenyl)-N'-(2-fluoro-5-trifluoromethylphenyl)guanidine;N-(3-ethylphenyl)-N,N'-dimethyl-N'-(2-chloro-5-ethylphenyl)guanidine;N-(3-ethylphenyl)-N-methyl-N'-(2-chloro-5-ethylphenyl)guanidine;N-(3-ethylphenyl)-N'-(2-chloro-5-ethylphenyl)guanidine;N-(3-ethylphenyl)-N,N'-dimethyl-N'-(2-bromo-5-ethylphenyl)guanidine;N-(3-ethylphenyl)-N-methyl-N'-(2-bromo-5-ethylphenyl)guanidine;N-(3-ethylphenyl)-N'-(2-bromo-5-ethylphenyl)guanidine;N-(3-ethylphenyl)-N,N'-dimethyl-N'-(2-fluoro-5-ethylphenyl)guanidine;N-(3-ethylphenyl)-N-methyl-N'-(2-fluoro-5-ethylphenyl)guanidine;N-(3-ethylphenyl)-N'-(2-fluoro-5-ethylphenyl)guanidine;N-(3-ethylphenyl)-N,N'-dimethyl-N'-(2-chloro-5-methylphenyl)guanidine;N-(3-ethylphenyl)-N-methyl-N'-(2-chloro-5-methylphenyl)guanidine;N-(3-ethylphenyl)-N'-(2-chloro-5-ethylphenyl)guanidine;N-(3-ethylphenyl)-N'-(2-chloro-5-methylphenyl)guanidine;N-(3-ethylphenyl)-N-methyl-N'-(2-chloro-5-methylthio)guanidine;N-(3-ethylphenyl)-N'-(2-chloro-5-methylthio)guanidine;N-(3-ethylphenyl)-N-methyl-N'-(2,4,5-trichlorophenyl)guanidine;N-(3-ethylphenyl)-N'-(2,4,5-trichlorophenyl)guanidine;N-(3-ethylphenyl)-N-methyl-N'-(2,3,5-trichlorophenyl)guanidine;N-(3-ethylphenyl)-N'-(2,3,5-trichlorophenyl)guanidine;N-(3-methylthiophenyl)-N-methyl-N'-(2-chloro-5-methylthiophenyl)guanidine;N-(3-methylthiophenyl)-N'-methyl-N'-(2-chloro-5-methylthiophenyl)guanidine;N-(3-methylthiophenyl)-N'-(2-chloro-5-methylthiophenyl)guanidine;N-(3-methylthiophenyl)-N-methyl-N'-(2-chloro-5-ethylphenyl)guanidine;N-(3-methylthiophenyl)-N'-methyl-N'-(2-chloro-5-ethylphenyl)guanidine;N-(3-methylthiophenyl)-N'-(2-chloro-5-ethylphenyl)guanidine;N-(3-methylthiophenyl)-N-methyl-N'-(2-bromo-5-ethylphenyl)guanidine;N-(3-methylthiophenyl)-N'-methyl-N'-(2-bromo-5-ethylphenyl)guanidine;N-(3-methylthiophenyl)-N'-(2-bromo-5-ethylphenyl)guanidine;N-(3-methylthiophenyl)-N-methyl-N'-(2,5-dichlorophenyl)guanidine;N-(3-methylthiophenyl-N'-methyl-N'-(2,5-dichlorophenyl)guanidine;N-(3-methylthiophenyl)-N'-(2,5-dichlorophenyl)guanidine;N-(3-methylthiophenyl)-N-methyl-N'-(2,5-dibromophenyl)guanidine;N-(3-methylthiophenyl)-N'-methyl-N'-(2,5-dibromophenyl)guanidine;N-(3-methylthiophenyl)-N'-(2,5-dibromophenyl)guanidine;N-(3-trifluoromethylphenyl)-N-methyl-N'-(2-chloro-5-methylthiophenyl)guanidine;N-(3-trifluoromethylphenyl)-N'-methyl-N'-(2-chloro-5-methylthiophenyl)guanidine;N-(3-trifluoromethylphenyl)-N'-(2-chloro-5-methylthiophenyl)guanidine;N-(3-trifluoromethylphenyl)-N-methyl-N'-(2-chloro-5-ethylphenyl)guanidine;N-(3-trifluoromethylphenyl)-N'-methyl-N'-(2-chloro-5-ethylphenyl)guanidine;N-(3-trifluoromethylphenyl)-N'-(2-chloro-5-ethylphenyl)guanidine;N-(3-trifluoromethylphenyl)-N-methyl-N'-(2-bromo-5-ethylphenyl)guanidine;N-(3-trifluoromethylphenyl)-N'-methyl-N'-(2-bromo-5-ethylphenyl)guanidine;N-(3-trifluoromethylphenyl)-N'-(2-bromo-5-ethylphenyl)guanidine;N-(3-trifluoromethylphenyl)-N-methyl-N'-(2,5-dichlorophenyl)guanidine;N-(3-trifluoromethylphenyl)-N'-methyl-N'-(2,5-dichlorophenyl)guanidine;N-(3-trifluoromethylphenyl)-N'-(2,5-dichlorophenyl)guanidine;N-(3-trifluoromethylphenyl)-N-methyl-N'-(2,5-dibromophenyl)guanidine;N-(3-trifluoromethylphenyl)-N'-methyl-N'-(2,5-dibromophenyl)guanidine;N-(3-trifluoromethylphenyl)-N'-(2,5-dibromophenyl)guanidine;N-(3-ethylphenyl)-N-methyl-N'-(2-bromo-5-methylthiophenyl)guanidine;N-(3-ethylphenyl)-N'-methyl-N'-(2-bromo-5-methylthiophenyl)guanidine;N-(3-ethylphenyl)-N'-(2-bromo-5-methylthiophenyl)guanidine;N-(3-methylthiophenyl)-N-methyl-N'-(2-bromo-5-methylthiophenyl)guanidine;N-(3-methylthiophenyl)-N'-methyl-N'-(2-bromo-5-methylthiophenyl)guanidine;N-(3-methylthiophenyl)-N'-(2-bromo-5-methylthiophenyl)guanidine;N-(3-methylthiophenyl)-N-methyl-N'-(2-bromo-5-ethylphenyl)guanidine;N-(3-methylthiophenyl)-N'-methyl-N'-(2-bromo-5-ethylphenyl)guanidine;N-(3-methylthiophenyl)-N'-(2-bromo-5-ethylphenyl)guanidine;N-(3-trifluoromethylphenyl)-N-methyl-N'-(2-bromo-5-methylthiophenyl)guanidine;N-(3-trifluoromethylphenyl)-N'-methyl-N'-(2-bromo-5-methylthiophenyl)guanidine;N-(3-trifluoromethylphenyl)-N'-(2-bromo-5-methylthiophenyl)guanidine;N-(3-bromophenyl)-N-methyl-N'-(2-chloro-5-methylthiophenyl)guanidine;N-(3-bromophenyl)-N'-methyl-N'-(2-chloro-5-methylthiophenyl)guanidine;N-(3-bromophenyl)-N'-(2-chloro-5-methylthiophenyl)guanidine;N-(3-trifluoromethoxyphenyl)-N-methyl-N'-(2,5-dibromophenyl)guanidine;N-(3-trifluoromethoxyphenyl)-N'-methyl-N'-(2,5-dibromophenyl)guanidine;N-(3-trifluoromethoxyphenyl)-N'-(2,5-dibromophenyl)guanidine;N-(3-trifluoromethoxyphenyl)-N-methyl-N'-(2-bromo-5-ethylphenyl)guanidine;N-(3-trifluoromethoxyphenyl)-N'-methyl-N'-(2-bromo-5-ethylphenyl)guanidine;N-(3-trifluoromethoxyphenyl)-N'-(2-bromo-5-ethylphenyl)guanidine;N-(3-iodophenyl)-N-methyl-N'-(2-chloro-5-methylthiophenyl)guanidine;N-(3-iodophenyl)-N'-methyl-N'-(2-chloro-5-methylthiophenyl)guanidine;N-(3-iodophenyl)-N'-(2-chloro-5-methylthiophenyl)guanidine;N-(3-iodophenyl)-N-methyl-N'-(2-chloro-5-ethylphenyl)guanidine;N-(3-iodophenyl)-N'-methyl-N'-(2-chloro-5-ethylphenyl)guanidine;N-(3-iodophenyl)-N'-(2-chloro-5-ethylphenyl)guanidine;N-(3-ethylphenyl)-N'-(2-chloro-5-ethylthiophenyl)guanidine;N-(3-ethylphenyl)-N-methyl-N'-(2-chloro-5-ethylthiophenyl)guanidine;N-(3-ethylphenyl)-N'-methyl-N'-(2-chloro-5-ethylthiophenyl)guanidine;N-(3-ethylphenyl)-N,N'-dimethyl-N'-(2-chloro-5-ethylthiophenyl)guanidine;N-(3-ethylphenyl)-N'-(2-bromo-5-ethylthiophenyl)guanidine;N-(3-ethylphenyl)-N-methyl-N'-(2-bromo-5-ethylthiophenyl)guanidine;N-(3-ethylphenyl)-N'-methyl-N'-(2-bromo-5-ethylthiophenyl)guanidine;N-(3-ethylphenyl)-N,N'-dimethyl-N'-(2-bromo-5-ethylthiophenyl)guanidine;N-(3-methylthiophenyl)-N'-(2-chloro-5-ethylthiophenyl)guanidine;N-(3-methylthiophenyl)-N-methyl-N'-(2-chloro-5-ethylthiophenyl)guanidine;N-(3-methylthiophenyl)-N'-methyl-N'-(2-chloro-5-ethylthiophenyl)guanidine;N-(3-methylthiophenyl)-N,N'-dimethyl-N'-(2-chloro-5-ethylthiophenyl)guanidine;N-(3-methylthiophenyl)-N'-(2-bromo-5-ethylthiophenyl)guanidine;N-(3-methylthiophenyl)-N-methyl-N'-(2-bromo-5-ethylthiophenyl)guanidine;N-(3-methylthiophenyl)-N'-methyl-N'-(2-bromo-5-ethylthiophenyl)guanidine;N-(3-methylthiophenyl)-N,N'-dimethyl-N'-(2-bromo-5-ethylthiophenyl)guanidine;N-(3-trifluoromethylphenyl)-N'-(2-chloro-5-ethylthiophenyl)guanidine;N-(3-trifluoromethylphenyl)-N-methyl-N'-(2-chloro-5-ethylthiophenyl)guanidine;N-(3-trifluoromethylphenyl)-N'-methyl-N'-(2-chloro-5-ethylthiophenyl)guanidine;N-(3-trifluoromethylphenyl)-N,N'-dimethyl-N'-(2-chloro-5-ethylthiophenyl)guanidine;N-(3-trifluoromethylphenyl)-N'-(2-bromo-5-ethylthiophenyl)guanidine;N-(3-trifluoromethylphenyl)-N-methyl-N'-(2-bromo-5-ethylthiophenyl)guanidine;N-(3-trifluoromethylphenyl)-N'-methyl-N'-(2-bromo-5-ethylthiophenyl)guanidine;N-(3-trifluoromethylphenyl)-N,N'-dimethyl-N'-(2-bromo-5-ethylthiophenyl)guanidine;N-(3-ethylphenyl)-N'-(2-chloro-5-trifluoromethylthiophenyl)guanidine;N-(3-ethylphenyl)-N-methyl-N'-(2-chloro-5-trifluoromethylthiophenyl)guanidine;N-(3-ethylphenyl)-N'-methyl-N'-(2-chloro-5-trifluoromethylthiophenyl)guanidine;N-(3-ethylphenyl)-N,N'-dimethyl-N'-(2-chloro-5-trifluoromethylthiophenyl)guanidine;N-(3-ethylphenyl)-N'-(2-bromo-5-trifluoromethylthiophenyl)guanidine;N-(3-ethylphenyl)-N-methyl-N'-(2-bromo-5-trifluoromethylthiophenyl)guanidine;N-(3-ethylphenyl)-N'-methyl-N'-(2-bromo-5-trifluoromethylthiophenyl)guanidine;N-(3-ethylphenyl)-N,N'-dimethyl-N'-(2-bromo-5-trifluoromethylthiophenyl)guanidine;N-(3-methylthiophenyl)-N'-(2-chloro-5-trifluoromethylthiophenyl)guanidine;N-(3-methylthiophenyl)-N-methyl-N'-(2-chloro-5-trifluoromethylthiophenyl)guanidine;N-(3-methylthiophenyl)-N'-methyl-N'-(2-chloro-5-trifluoromethylthiophenyl)guanidine;N-(3-methylthiophenyl)-N,N'-dimethyl-N'-(2-chloro-5-trifluoromethylthiophenyl)guanidine;N-(3-methylthiophenyl)-N'-(2-bromo-5-trifluoromethylthiophenyl)guanidine;N-(3-methylthiophenyl)-N-methyl-N'-(2-bromo-5-trifluoromethylthiophenyl)guanidine;N-(3-methylthiophenyl)-N'-methyl-N'-(2-bromo-5-trifluoromethylthiophenyl)guanidine;N-(3-methylthiophenyl)-N,N'-dimethyl-N'-(2-bromo-5-trifluoromethylthiophenyl)guanidine;N-(3-trifluoromethylphenyl)-N'-(2-chloro-5-trifluoromethylthiophenyl)guanidine;N-(3-trifluoromethylphenyl)-N-methyl-N'-(2-chloro-5-trifluoromethylthiophenyl)guanidine;N-(3-trifluoromethylphenyl)-N'-methyl-N'-(2-chloro-5-trifluoromethylthiophenyl)guanidine;N-(3-trifluoromethylphenyl)-N,N'-dimethyl-N'-(2-chloro-5-trifluoromethylthiophenyl)guanidine;N-(3-trifluoromethylphenyl)-N'-(2-bromo-5-trifluoromethylthiophenyl)guanidine;N-(3-trifluoromethylphenyl)-N-methyl-N'-(2-bromo-5-trifluoromethylthiophenyl)guanidine;N-(3-trifluoromethylphenyl)-N'-methyl-N'-(2-bromo-5-trifluoromethylthiophenyl)guanidine;orN-(3-trifluoromethylphenyl)-N,N'-dimethyl-N'-(2-bromo-5-trifluoromethylthiophenyl);guanidine;N-(1-naphthyl)-N'-(2-bromo-5-ethylphenyl)guanidine;N-(1-naphthyl-N'-(2-fluoro-5-ethylphenyl)guanidine;N-(1-naphthyl)-N'-(2,5-dichlorophenyl)guanidine;N-(1-naphthyl)-N'-(2,4,5-trichlorophenyl)guanidine;N-(1-naphthyl)-N'-(2,3,5-trichlorophenyl)guanidine;N-(1-naphthyl)-N'-(2,5-dichlorophenyl)-N'-methylguanidine;N-(1-naphthyl)-N'-(2-chloro-5-methylphenyl)guanidine;N-(1-naphthyl)-N'-(2,5-dimethylphenyl)guanidine;N-(1-naphthyl)-N'-(2,5-dibromophenyl)guanidine;N-(1-naphthyl)-N'-(2-chloro-5-methylphenyl)-N'-methylguanidine;N-(1-naphthyl)-N'-(2,5-dimethylphenyl)-N'-methylguanidine;N-(1-naphthyl)-N'-(2,5-dibromophenyl)-N-methylguanidine;N-(1-naphthyl)-N'-(2,5-dibromophenyl)-N'-methylguanidine;N-(1-naphthyl)-N'-(2-chloro-5-methylthiophenyl)guanidine;N-(1-naphthyl)-N'-(2-fluoro-5-trifluoromethylphenyl)guanidine;N-(1-naphthyl)-N'-(2-chloro-5-trifluoromethylphenyl)guanidine;N-(1-naphthyl)-N'-(2-bromo-5-trifluoromethylphenyl)guanidine;N-(1-naphthyl)-N'-(2-methylthio-5-trifluoromethylphenyl)guanidine;N-(1-naphthyl)-N'-(2-methoxy-5-methylphenyl)guanidine;N-(1-naphthyl)-N'-(2-chloro-5-ethylphenyl)guanidine;N-(1-naphthyl)-N'-(2-chloro-5-ethylphenyl)-N'-methylguanidine;N-(1-naphthyl)-N'-methyl-N'-(2-chloro-5-methylthiophenyl)guanidine;N-(8-quinolinyl)-N'-(2-chloro-5-methylphenyl)guanidine;N-(8-quinolinyl)-N'-(2-chloro-5-ethylphenyl)guanidine;N-(8-quinolinyl)-N'-methyl-(2-chloro-5-ethylphenyl)guanidine;N-(1-naphthyl)-N'-(2-fluoro-5-methylphenyl)guanidine;N-(1-naphthyl)-N'-(2-chloro-5-methylthiophenyl)guanidine;N-(1-naphthyl)-N'-(2-iodo-5-methylthiophenyl)guanidine; orN-(1-naphthyl)-N'-(2-bromo-5-methylthiophenyl)guanidine; andpharmaceutically acceptable salts of said compounds.
 25. A method ofclaim 4 wherein the compoundis:N-(3-methylsulfonylphenyl)-N-methyl-N'-(2,5-dibromophenyl)guanidine;N-(3-methylsulfonylphenyl)-N'-methyl-N'-(2,5-dibromophenyl)guanidine;N-(3-methylsulfonylphenyl)-N'-(2,5-dibromophenyl)guanidine;N-(3-methylsulfinylphenyl)-N-methyl-N'-(2,5-dibromophenyl)guanidine;N-(3-methylsulfinylphenyl)-N'-methyl-N'-(2,5-dibromophenyl)guanidine; orN-(3-methylsulfinylphenyl)-N'-(2,5-dibromophenyl)guanidine; andpharmaceutically acceptable salts thereof.
 26. A method of inhibitingNMDA receptor-ion channel related neurotoxicity in a mammal exhibitingsuch neurotoxicity or susceptible thereto comprising administering tothe mammal an effective amount of a compound of the following formula:##STR18## wherein R is substituted or unsubstituted carbocyclic aryl,substituted or unsubstituted aralkyl, or a substituted or unsubstitutedheteroaromatic or heterocyclic group having 1 to 3 rings, 3 to 8 ringmembers in each ring and 1 to 3 heteroatoms;R¹ and R² are eachindependently hydrogen, substituted or unsubstituted alkyl, substitutedor unsubstituted alkenyl, substituted or unsubstituted alkynyl,substituted or unsubstituted alkoxy, substituted or unsubstitutedalkylthio, substituted or unsubstituted alkylsulfinyl, substituted orunsubstituted alkylsulfonyl, substituted or unsubstituted aminoalkyl,substituted or unsubstituted carbocyclic aryl, substituted orunsubstituted aralkyl, or a substituted or unsubstituted heteroaromaticor heteroalcyclic group having 1 to 3 rings, 3 to 8 ring members in eachring and 1 to 3 hetero atoms; R³ R⁴, and each R⁵ substituent are eachindependently nitro, cyano, halogen, hydroxyl, azido, substituted orunsubstituted alkyl, substituted or unsubstituted alkenyl, substitutedor unsubstituted alkynyl, substituted or unsubstituted alkanoyl,substituted or unsubstituted carboxyl, substituted or unsubstitutedalkoxy, substituted or unsubstituted alkylthio, substituted orunsubstituted alkylsulfinyl, substituted or unsubstituted alkylsulfonyl,substituted or unsubstituted aminoalkyl, substituted or unsubstitutedcarbocyclic aryl, or substituted or unsubstituted aralkyl, with at leastone of R³, R⁴, R⁵ being nitro, cyano, substituted or unsubstitutedalkanoyl or substituted or unsubstituted carboxyl; n is an integer offrom 0-3; or a pharmaceutically acceptable salt thereof, with theexclusion of N-(2,4-di-iodo-5-hydxroxyphenyl)-N'-(2-tolyl)-guanidine andN-(2-methoxy-5-ethylphenyl)-N'-naphthylguanidine.
 27. A method of claim26 wherein the neurotoxicity is caused by hypoxia, hypoglycemia, brainor spinal cord ischemia or brain or spinal cord trauma.
 28. A method oftreating a mammal suffering from nerve cell death, stroke, heart attack,brain or spinal cord trauma, brain or spinal cord ischemia comprisingadministering to the mammal a treatment effective amount of thefollowing formula: ##STR19## wherein R is substituted or unsubstitutedcarbocyclic aryl, substituted or unsubstituted aralkyl, or a substitutedor unsubstituted heteroaromatic or heterocyclic group having 1 to 3rings, 3 to 8 ring members in each ring and 1 to 3 heteroatoms;R¹ and R²are each independently hydrogen, substituted or unsubstituted alkyl,substituted or unsubstituted alkenyl, substituted or unsubstitutedalkynyl, substituted or unsubstituted alkoxy, substituted orunsubstituted alkylthio, substituted or unsubstituted alkylsulfinyl,substituted or unsubstituted alkylsulfonyl, substituted or unsubstitutedaminoalkyl, substituted or unsubstituted carbocyclic aryl, substitutedor unsubstituted aralkyl, or a substituted or unsubstitutedheteroaromatic or heteroalicyclic group having 1 to 3 rings, 3 to 8 ringmembers in each ring and 1 to 3 hetero atoms; R³, R⁴, and each R⁵substituent are each independently nitro, cyano, halogen, hydroxyl,azido, substituted or unsubstituted alkyl, substituted or unsubstitutedalkenyl, substituted or unsubstituted alkynyl, substituted orunsubstituted alkanoyl, substituted or unsubstituted carboxyl,substituted or unsubstituted alkoxy, substituted or unsubstitutedalkylthio, substituted or unsubstituted alkylsulfinyl, substituted orunsubstituted alkylsulfonyl, substituted or unsubstituted aminoalkyl,substituted or unsubstituted carbocyclic aryl, or substituted orunsubstituted aralkyl, with at least one of R³, R⁴, R⁵ being nitro,cyano, substituted or unsubstituted alkanoyl or substituted orunsubstituted carboxyl; n is an integer of from 0-3; or apharmaceutically acceptable salt thereof, with the exclusion ofN-(2,4-di-iodo-5-hydroxyphenyl)-N'-(2-tolyl)-guanidine andN-(2-methoxy-5-ethylphenyl)-N'-naphthylguanidine.
 29. A compound of anyone of claims 1, 3, 4 or 14 wherein R is substituted or unsubstitutedcourmarinyl, quinolinyl, pyridyl, pyrazinyl, pyrimidyl, furyl, pyrrolyl,thienyl, thiazolyl, oxazolyl, imidazolyl, indolyl, benzofuranyl,benzothiazol, tetrahydrofuranyl, tetrahydropyranyl, piperdinyl,morpholino, pyrrolindinyl or aralkyl having 1-3 separate or fused ringsand from 6 to about 18 carbon ring atoms.
 30. A compound of any one ofclaims 1, 3, 4 or 14 wherein the substituents may be optionallysubstituted by one or more halogen, cyano, hydroxyl, nitro, azido,alkanoyl, carboxamido, alkyl, alkenyl, alkynyl, alkoxy, aryloxy,alkylthio or aminoalkyl.
 31. The method of claim 10 wherein the compoundisN-(3-methylthiophenyl)-N-methyl-N'-(2-chloro-5-methylthiophenyl)guanidineor a pharmaceutically acceptable salt thereof.
 32. The method of any oneof claims 1, 3, 6, 7, 8, 9 or 10 wherein the compound isN-(3-methylphenyl)-N-methyl-N'-(2,5-dibromophenyl)guanidine or apharmaceutically acceptable salt thereof.
 33. A method of any one ofclaims 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 13, 14, 18, 19, 20, 21, 22, 23,25, 26, 27, 28, or 31, wherein the compound is administeredtransdermally.
 34. A method of claim 11 wherein the compound isadministered transdermally.
 35. A method of claim 12 wherein thecompound is administered transdermally.
 36. A method of claim 15 whereinthe compound is administered transdermally.
 37. A method of claim 16wherein the compound is administered transdermally.
 38. A method ofclaim 17 wherein the compound is administered transdermally.
 39. Amethod of claim 24 wherein the compound is administered transdermally.40. A method of claim 29 wherein the compound is administeredtransdermally.
 41. A method of claim 30 wherein the compound isadministered transdermally.
 42. A method of claim 32 wherein thecompound is administered transdermally.